Novel macrocycles as factor xia inhibitors

ABSTRACT

The present invention provides compounds of Formula (Ia): 
     
       
         
         
             
             
         
       
     
     or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/236,973, filed Feb. 4, 2014, which is a national phase ofInternational Patent Application No. PCT/US2012/049706, filed Aug. 6,2012, which claims priority to provisional application, U.S. Ser. No.61/515,401, filed on Aug. 5, 2011 incorporated by reference herein intheir entirety.

FIELD OF THE INVENTION

The present invention relates generally to novel macrocyclic compounds,and their analogues thereof, which are inhibitors of factor XIa and/orplasma kallikrein, compositions containing them, and methods of usingthem, for example, for the treatment or prophylaxis of thromboembolicdisorders.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), andsynthetic pentasaccharides and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®). The oral anticoagulant warfarin, inhibits thepost-translational maturation of coagulation factors VII, IX, X andprothrombin, and has proven effective in both venous and arterialthrombosis. However, its usage is limited due to its narrow therapeuticindex, slow onset of therapeutic effect, numerous dietary and druginteractions, and a need for monitoring and dose adjustment. Thusdiscovering and developing safe and efficacious oral anticoagulants forthe prevention and treatment of a wide range of thromboembolic disordershas become increasingly important.

One approach is to inhibit thrombin generation by targeting theinhibition of coagulation factor XIa (FXIa). Factor XIa is a plasmaserine protease involved in the regulation of blood coagulation, whichis initiated in vivo by the binding of tissue factor (TF) to factor VII(FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa complexactivates factor IX (FIX) and factor X (FX) that leads to the productionof factor Xa (FXa). The generated FXa catalyzes the transformation ofprothrombin into small amounts of thrombin before this pathway is shutdown by tissue factor pathway inhibitor (TFPI). The process ofcoagulation is then further propagated via the feedback activation ofFactors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. etal., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) Theresulting burst of thrombin converts fibrinogen to fibrin thatpolymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIaplays a key role in propagating this amplification loop and is thus anattractive target for anti-thrombotic therapy.

SUMMARY OF THE INVENTION

The present invention provides novel macrocyclic compounds, theiranalogues, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof, which are useful as selectiveinhibitors of serine protease enzymes, especially factor XIa and/orplasma kallikrein.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of thromboembolic disorders.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a thromboembolicdisorder.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two, other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present invention provides compounds of Formula(I):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is selected from aryl and a 5- to 6-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), S(O)_(p), and O, wherein said aryl and heterocycle areoptionally substituted with one or more R¹ as valence allows;

ring B is a 5- to 6-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NH, S(O)_(p), and O, wherein saidheterocycle are optionally substituted with one or more R¹⁰ as valenceallows;

ring C is a 4- to 5-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O, wherein saidheterocycle are optionally substituted with one or more R² as valenceallows;

X¹ is selected from C₁₋₄ alkylene and C₂₋₄ alkenylene; optionally one ormore of the carbon atoms of said alkylene and alkenylene may be replacedby O, S(O)_(p), NH, and N(C₁₋₄ alkyl);

R¹ is, independently at each occurrence, selected from H, halogen, NO₂,C₁₋₆ alkyl, OH, OMe, and CN;

R² is selected from H, ═O, OH, NH₂, CF₃, halogen, and C₁₋₄ alkyl(optionally substituted with OH), C₁₋₃ alkoxy, and C(O)C₁₋₃ alkyl;

R³ is selected from H and C₁₋₄ alkyl;

alternatively, R² and R³, together with the atoms to which they aredirectly or indirectly attached, form a ring wherein said ring isoptionally substituted with ═O;

R⁴ is selected from H, C₁₋₄ alkyl, hydroxyl, and C₃₋₆ cycloalkyl;

R⁵ is selected from H and C₁₋₄ alkyl;

R⁶ is selected from H, halogen, C(O)OH, and C(O)O(C₁₋₄ alkyl);

R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;

alternatively, R⁶ and R⁷ together are ═O;

R⁸ is, independently at each occurrence, selected from H, halogen,NHC(O)O—C₁₋₄ alkyl, CN, OH, O—C₁₋₄ alkyl; CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(CH₂)₁₋₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₁₋₃O(C₁₋₄ alkyl), NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),—NHCO₂(CH₂)₁₋₂OH, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, NHC(O)NH(C₁₋₄ alkyl)N[5- to 6-memberedheterocycle)], —NHSO₂(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, and —CH₂CONH₂;

R⁹ is selected from H and C₁₋₄ alkyl;

R¹⁰ is, independently at each occurrence, selected from H, halogen, CN,OH, ═O, NH₂, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, CF₃, CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), and CONH; and

p is, independently at each occurrence, selected from 0, 1, and 2;

provided the following compounds are excluded

In a second aspect, the present invention provides compounds of Formula(II):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspect,wherein:

ring A is selected from aryl and a 6-membered heterocycle comprising:carbon atoms and 1-3 heteroatoms selected from N, NH, and N(C₁₋₄ alkyl);

ring B is selected from imidazole, pyridine, pyridone, and pyridazine;

X¹ is selected from CH₂ and CH═CH;

W and Q are each independently selected from N, NR⁹, CR², and CHR²; and

R^(2a) is selected from H, NH₂, and C₁₋₄ alkyl.

In a third aspect, the present invention provides compounds of Formula(II), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the second aspect,wherein:

ring A is selected from phenyl and piperidine;

is independently selected from

and

R¹⁰ is selected from H, halogen, and CN.

In a fourth aspect, the present invention provides compounds of Formula(III):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the third aspect,wherein:

is independently selected from

W and Q are each independently selected from N and CR²;

R^(1a) and R^(1b) are each independently selected from H and halogen;

R² is independently at each occurrence, selected from H and C₁₋₄ alkyloptionally substituted with OH;

R^(2a) is selected from H, NH₂, and Me;

R⁴ is selected from H and C₁₋₄ alkyl;

R⁵ is selected from H and C₁₋₄ alkyl;

R⁶ is independently selected from H, C(O)OH, and C(O)O(C₁₋₄ alkyl);

R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;

alternatively, R⁶ and R⁷ together are ═O; and

R¹⁰ is selected from H, halogen and CN.

In a fifth aspect, the present invention provides compounds of Formula(IV):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the fourth aspect,wherein:

W and Q are each independently selected from N and CH;

R^(1a) and R^(1b) are each independently selected from H, F, and Cl;

R⁴ is selected from H, methyl, ethyl, propyl, isopropyl, and butyl;

R⁵ is H;

R⁸ is NHC(O)O—C₁₋₄ alkyl; and

R¹⁰ is selected from H and CN.

In a sixth aspect, the present invention provides compounds of Formula(V):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the fifth aspect,wherein:

R^(1a) is selected from H and F;

R^(1b) is Cl; and

R⁴ is selected from H, methyl, ethyl, and isopropyl.

In a seventh aspect, the present invention provides compounds of Formula(VI):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the fourth aspect,wherein;

is independently selected from

W is selected from N and CH;

Q is selected from N and CH;

R^(1a) and R^(1b) are each independently selected from F and Cl;

R⁴ is selected from H, methyl, and ethyl; and

R⁸ is NHC(O)OMe.

In another aspect, the present invention provides compounds of Formula(Ia):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is selected from aryl and a 5- to 6-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), S(O)_(p), and O, wherein said aryl and heterocycle areoptionally substituted with R¹;

ring B is a 5- to 6-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NH, S(O)_(p), and O, wherein saidheterocycle is optionally substituted with R¹⁰;

ring C is a 4- to 6-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O, wherein saidheterocycle is optionally substituted with R²;

X is selected from C₄₋₈ alkylene and C₄₋₈ alkenylene, wherein saidalkylene and alkenylene are substituted with R⁴ and R⁵; alternativelyone or more of the carbon atoms of said alkylene and alkenylene may bereplaced by O, C═O, S(O)_(p), NH, and N(C₁₋₄ alkyl);

Y is selected from —CR⁶R⁷—NH— and —NH—CR⁶R⁷—;

R¹ is selected from H, halogen, NO₂, C₁₋₆ alkyl, OH, haloalkyl, alkoxy,haloalkoxy, —C(═O)C₁₋₃ alkyl, and CN;

R² is selected from H, ═O, OH, NH₂, CF₃, halogen, C₁₋₄ alkyl (optionallysubstituted with OH), C₁₋₃ alkoxy, and C(O)C₁₋₃ alkyl;

R³ is selected from H and C₁₋₄ alkyl;

alternatively, R² and R³, together with the atoms to which they aredirectly or indirectly attached, form a ring;

R⁴ and R⁵ are independently selected from H, halogen, C₁₋₆ alkyl, OH,NH₂, —CH₂NH₂, C₁₋₄ haloalkyl, —OCH₂F, —OCHF₂, —OCF₃, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, —CH₂OH, and —CH₂O(C₁₋₄ alkyl); when R⁴ andR⁵ are not attached to the same carbon atom, they may be taken togetherwith the carbon atoms to which they are attached to form a carbocycle;

R⁶ is selected from H, halogen, C(O)OH, and C(O)O(C₁₋₄ alkyl);

R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;

alternatively, R⁶ and R⁷ together are ═O;

R⁸ is, independently at each occurrence, selected from H, halogen,haloalkyl, CN, —(CH₂)_(n)OH, NR¹²R¹², —CH₂NH₂, C(O)OH,—(CH₂)_(n)—NHC(O)OR¹², —NHC(O)R¹², —NHC(O)C(O)R¹², —NHC(N—CN)NHR¹²,—NHC(NH)NHR¹², —N═CHNR¹²R¹², —NHC(O)NR¹²R¹², —NHS(O)₂C₁₋₄ alkyl,—(CH₂)_(n)—CONR¹²R¹², —(CH₂)_(n)C(O)O(C₁₋₄ alkyl),—NHC(O)OCH₂(C(CH₂)₂)O—(CH₂)_(n)—C₃₋₁₀ carbocycle, —(CH₂)_(n)—C₃₋₁₀carbocycle, and —(CH₂)_(n)-4-10-membered heterocycle wherein saidcarbocycle and heterocycle are optionally substituted with R¹³;

R⁹ is selected from H and C₁₋₄ alkyl;

R¹⁰ is selected from H, halogen, CN, ═O, OH, NH₂, C₃₋₆ cycloalkyl, C₁₋₄alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl;

R¹¹ is selected from H, halogen, and methyl;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with halogen,hydroxy, alkoxy, carboxy, alkoxycarbonyl), —(CH₂)_(n)—C₃₋₁₀ carbocycleand —(CH₂)_(n)-4-10-membered heterocycle, wherein said carbocycle andheterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O;

n is, independently at each occurrence, selected from 0, 1, 2, 3, and 4;

p is, independently at each occurrence, selected from 0, 1, and 2;

provided the following compounds are excluded

In another aspect, the present invention provides compounds of Formula(Ia), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring C is a 6-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, and NR⁹, wherein said heterocycle isoptionally substituted with R² and wherein all the variables have themeanings as defined in Formula (Ia).

In another aspect, the present invention provides compounds of Formula(Ia), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁸ is, independently at each occurrence, selected from haloalkyl,—CH₂OH, NR¹²R¹², —(CH₂)_(n)—NHC(O)OR¹², —NHC(O)R¹², —NHC(O)C(O)R¹²,—NHC(N—CN)NHR¹², —NHC(NH)NHR¹², —N═CHNR¹²R¹², —(CH₂)_(n)—C₃₋₁₀carbocycle, and —(CH₂)_(n)-4-10-membered heterocycle wherein saidcarbocycle and heterocycle are optionally substituted with R¹³;

X is selected from —CR⁴R⁵—CR⁴R⁵—, —CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—, and—CR⁴═CR⁵CR⁴R⁵—, wherein one or more —CR⁴R⁵— may be replaced by O or C═O;

R⁴ is selected from H, F, Cl, OH, and C₁₋₄ alkyl;

R⁵ is selected from H, F, and C₁₋₄ alkyl; when R⁴ and R⁵ are notattached to the same carbon atom, they may be taken together with thecarbon atoms to which they are attached to form a carbocycle;

R¹¹ is H;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with halogen,hydroxy, alkoxy, carboxy, alkoxycarbonyl), —(CH₂)_(n)—C₃₋₁₀ carbocycleand —(CH₂)_(n)-4-10-membered heterocycle, wherein said carbocycle andheterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3,and

wherein all the variables have the meanings as defined in Formula (Ia).

In another aspect, the present invention provides compounds of Formula(IIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is selected from aryl and a 5- to 6-membered heterocyclecomprising: carbon atoms and 1-3 heteroatoms selected from N, NH, andN(C₁₋₄ alkyl);

ring B is selected from imidazole, pyridine, pyridone, pyrimidine, andpyridazine;

X^(1a) is selected from C₂₋₄ alkylene and C₂₋₄ alkenylene wherein saidC₂₋₄ alkylene and C₂₋₄ alkenylene are optionally substituted with R⁴ andR⁵; alternatively, one or more of the carbon atoms of said alkylene maybe replaced by O and C═O;

U, V, W, and Q are each independently selected from N, NR⁹, S, O, C,CR², and CHR²;

--- is an optional bond;

R¹ is, independently at each occurrence, selected from H, halogen, NO₂,C₁₋₆ alkyl, OH, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and CN;

R² is selected from H, ═O, OH, NH₂, CF₃, halogen, C₁₋₄ alkyl optionallysubstituted with OH, C₁₋₃ alkoxy, and C(O)C₁₋₃ alkyl;

R³ is H;

R⁴ and R⁵ are independently selected from H, halogen, C₁₋₆ alkyl, OH,and NH₂; when R⁴ and R⁵ are not attached to the same carbon atom, theymay be taken together with the carbon atoms to which they are attachedto form a carbocycle;

R⁶ is selected from H, halogen, C(O)OH, and C(O)O(C₁₋₄ alkyl);

R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;

alternatively, R⁶ and R⁷ together are ═O;

R⁸ is, independently at each occurrence, selected from H, halogen,haloalkyl, CN, OH, NR¹²R¹², C(O)OH, —(CH₂)_(n)—NHC(O)OR¹², —NHC(O)R¹²,—NHC(O)NR¹²R¹², —NHS(O)₂C₁₋₄ alkyl, —(CH₂)_(n)—CONR¹²R¹²,—(CH₂)_(n)C(O)O(C₁₋₄ alkyl), —(CH₂)_(n)—C₃₋₁₀ carbocycle, and—(CH₂)_(n)-4-10-membered heterocycle optionally substituted with R¹³;

R⁹ is selected from H and C₁₋₄ alkyl;

R¹⁰ is, independently at each occurrence, selected from H, halogen, CN,═O, OH, NH₂, C₃₋₆ cycloalkyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkyl;

R¹¹ is H;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with halogen,hydroxy, alkoxy, carboxy, alkoxycarbonyl), —(CH₂)_(n)—C₃₋₁₀ carbocycleand —(CH₂)_(n)-4-10-membered heterocycle, wherein said carbocycle andheterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(IIa), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is selected from phenyl, piperidine, and pyridine;

is selected from

and

R¹⁰ is selected from H, F, Cl, C₁₋₄ alkyl, C₁₋₄ alkoxy, and CN.

In another aspect, the present invention provides compounds of Formula(IIIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

is independently selected from

U, V, W, and Q are each independently selected from N, NR⁹, S, C, CR²,and CHR²;

X^(1a) is selected from —CR⁴R⁵—CR⁴R⁵—, —CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—, and—CR⁴═CR⁵CR⁴R⁵—, wherein one or more —CR⁴R⁵— may be replaced by O or C═O;

R^(1a) and R^(1b) are each independently selected from H, halogen, OH,CN, CH₃, OCH₃, CF₃, and OCHF₂;

R² is selected from H, OH, NH₂, CF₃, halogen, C₁₋₄ alkyl (optionallysubstituted with OH), C₁₋₃ alkoxy, and C(O)C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, OH, and C₁₋₄ alkyl;

R⁵ is selected from H, F, and C₁₋₄ alkyl;

R⁶ is independently selected from H, C(O)OH, and C(O)O(C₁₋₄ alkyl);

R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;

alternatively, R⁶ and R⁷ together are ═O;

R⁸ is, independently at each occurrence, selected from H, halogen,haloalkyl, CN, OH, NR¹²R¹², —CH₂NH₂, C(O)OH, and —NHC(O)OR¹²,—(CH₂)_(n)—C₃₋₁₀ carbocycle, and —(CH₂)_(n)-4-10-membered heterocycleoptionally substituted with R¹³;

R⁹ is selected from H and C₁₋₄ alkyl;

R¹⁰ is selected from H, halogen, methyl, ethyl, methoxy, ethoxy, and CN;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with F, OH,—O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)), —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-4-10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(IVa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

is independently selected from

W and Q are each independently selected from N and CR²;

R^(1a) is selected from H, F, and Cl;

R^(1b) is selected from H, F, Cl, OH, CN, CH₃, OCH₃, CF₃, and OCHF₂;

R² is selected from H, OH, NH₂, CF₃, F, Cl, and C₁₋₄ alkyl;

R⁴ is selected from H, F, methyl, ethyl, propyl, and isopropyl;

R⁵ is H and F;

R⁸ is, independently at each occurrence, selected from H, halogen,haloalkyl, CN, OH, NR¹²R¹², C(O)OH, and —NHC(O)OR¹², and—(CH₂)_(n)-4-10-membered heterocycle optionally substituted with R¹³;

R¹⁰ is selected from H, halogen, methyl, ethyl, methoxy, ethoxy, and CN;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with F, OH,—O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)), —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-4-10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(Va):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

is independently selected from

Q is selected from N and CR²;

R^(1a) is selected from H and F;

R^(1b) is Cl;

R² is selected from H, OH, NH₂, F, Cl, and methyl;

R⁴ is selected from H, OH, methyl, ethyl, and isopropyl;

R⁵ is H and F;

R⁸ is, independently at each occurrence, selected from H, NR¹²R¹²,C(O)OH, —NHC(O)OR¹², and —(CH₂)_(n)-4-10-membered heterocycle optionallysubstituted with R¹³;

R¹⁰ is selected from H, halogen, methyl, ethyl, methoxy, ethoxy, and CN;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with F, OH,—O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)), —(CH₂)_(n)—C₃₋₁₀carbocycle, and —(CH₂)_(n)-4-10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(Vab):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁸ is selected from C(O)OH and a 4-10-membered heterocycle optionallysubstituted with R¹³.

In another aspect, the present invention provides compounds of Formula(VIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

is independently selected from

R^(1a) is selected from H and F;

R^(1b) is Cl;

R² is selected from H, OH, NH₂, F, Cl, and methyl;

R⁴ is selected from H, OH, methyl, ethyl, and isopropyl;

R⁵ is H and F;

R⁸ is, independently at each occurrence, selected from H, NR¹²R¹²,C(O)OH, and —NHC(O)OR¹²;

R¹⁰ is selected from H, halogen, methyl, ethyl, methoxy, ethoxy, and CN;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with F, OH,—O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)), —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-4-10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(VIIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

is independently selected from

W is selected from N and CR²;

Q is selected from N and CR²;

R^(1a) is selected from H and F;

R^(1b) is Cl;

R² is selected from H, Cl, NH₂, and methyl;

R⁴ is selected from H, F, methyl, ethyl, OH;

R⁵ is selected from H and F;

R⁸ is selected from H, NHR¹², —(CH₂)_(n)OH, —NHC(N—CN)NHR¹², —C(O)OH,and —NHC(O)OR¹², and —(CH₂)_(n)-4-10-membered heterocycle optionallysubstituted with R¹³;

R¹⁰ is selected from H, F, Cl, C₁₋₂ alkyl, methoxy, ethoxy, and CN;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with F, OH,—OC₁₋₄ alkyl, —C(O)OH, —C(O)OC₁₋₄ alkyl, —O-arylalkyl), —(CH₂)_(n)—C₃₋₆cycloalkyl and —(CH₂)_(n)-4-6-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄ alkyl), and Owherein said heterocycle is optionally substituted with R¹³;

R¹³ is selected from OH, OC₁₋₄ alkyl, C₁₋₆ alkyl (optionally substitutedwith alkoxy), C₃₋₆ cycloalkyl, and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(VIIa) or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate thereof, wherein:

is independently selected from

W is selected from N and CR²;

Q is selected from N and CR²;

R^(1a) is selected from H and F;

R^(1b) is Cl;

R² is selected from H, Cl, NH₂, and methyl;

R⁴ is selected from H, F, methyl, ethyl, OH;

R⁵ is selected from H and F;

R⁸ is selected from H, NHR¹², —C(O)OH, and —NHC(O)OR¹²;

R¹⁰ is selected from H, F, Cl, methyl methoxy, ethoxy, and CN;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with F, OH,—OC₁₋₄ alkyl, —C(O)OH, —C(O)OC₁₋₄ alkyl), —(CH₂)_(n)—C₃₋₆ cycloalkyl and—(CH₂)_(n)-4-6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), and O wherein saidheterocycle is optionally substituted with R¹³;

R¹³ is selected from OH, OC₁₋₄ alkyl, C₁₋₆ alkyl (optionally substitutedwith alkoxy), C₃₋₆ cycloalkyl, and ═O; and

n is, independently at each occurrence, selected from 0, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(VIIIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring B is a 5- to 6-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NH, S(O)_(p), and O, wherein saidheterocycle is optionally substituted with R¹⁰;

ring C is a 4- to 6-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O, wherein saidheterocycle is optionally substituted with R²;

X is selected from C₄₋₈ alkylene and C₄₋₈ alkenylene, wherein saidalkylene and alkenylene are substituted with R⁴ and R⁵; alternativelyone or more of the carbon atoms of said alkylene and alkenylene may bereplaced by O, C═O, S(O)_(p), NH, and N(C₁₋₄ alkyl);

Y is selected from —CR⁶R⁷—NH— and —NH—CR⁶R⁷—;

R^(1b) is selected from H and Cl;

R² is selected from H, ═O, OH, NH₂, CF₃, halogen, C₁₋₄ alkyl (optionallysubstituted with OH), C₁₋₃ alkoxy, and C(O)C₁₋₃ alkyl;

R³ is selected from H and C₁₋₄ alkyl;

R⁴ and R⁵ are independently selected from H, halogen, C₁₋₆ alkyl, OH,NH₂, —CH₂NH₂, C₁₋₄ haloalkyl, —OCH₂F, —OCHF₂, —OCF₃, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, —CH₂OH, and —CH₂O(C₁₋₄ alkyl); when R⁴ andR⁵ are not attached to the same carbon atom, they may be taken togetherwith the carbon atoms to which they are attached to form a carbocycle;

R⁶ is selected from H, halogen, C(O)OH, and C(O)O(C₁₋₄ alkyl);

R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;

alternatively, R⁶ and R⁷ together are ═O;

R⁸ is, independently at each occurrence, selected from H, halogen,haloalkyl, CN, —(CH₂)_(n)OH, NR¹²R¹², —CH₂NH₂, C(O)OH,—(CH₂)_(n)—NHC(O)OR¹², —NHC(O)R¹², —NHC(O)C(O)R¹², —NHC(═N—CN)NHR¹²,—NHC(═N—CN)NHR¹², —N═CHNR¹²R¹², —NHC(O)NR¹²R¹², —NHS(O)₂C₁₋₄ alkyl,—(CH₂)_(n)—CONR¹²R′, —(CH₂)_(n)C(O)O(C₁₋₄ alkyl), —(CH₂)_(n)—C₃₋₁₀carbocycle, and —(CH₂)_(n)-4-10-membered heterocycle wherein saidcarbocycle and heterocycle are optionally substituted with R¹³;

R⁹ is selected from H and C₁₋₄ alkyl;

R¹⁰ is selected from H, halogen, CN, ═O, OH, NH₂, C₃₋₆ cycloalkyl, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, CH₂OH, C(O)OH, C(O)O(C₁₋₄ alkyl),and CONH;

R¹¹ is selected from H, halogen, and methyl;

R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with halogen,hydroxy, alkoxy, carboxy, alkoxycarbonyl), —(CH₂)_(n)—C₃₋₁₀ carbocycleand —(CH₂)_(n)-4-10-membered heterocycle, wherein said carbocycle andheterocycle are optionally substituted with R¹³;

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O;

n is, independently at each occurrence, selected from 0, 1, 2, 3, and 4;

p is, independently at each occurrence, selected from 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(IIa) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein

ring A is

X^(1a) is selected from —CR⁴R⁵—CR⁴R⁵—, —CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—, and—CR⁴═CR⁵CR⁴R⁵—, wherein one or more —CR⁴R⁵— may be replaced by O or C═O.All other variables have the meanings as defined in Formula (IIa).

In another aspect, the present invention provides compounds of Formula(IXa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein the variables have the meaningsas defined in Formula (IIa).

In one embodiment, the present invention provides compounds of Formula(I) or (II), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

ring A is selected from piperidine and phenyl optionally substitutedwith R¹;

R¹ is, independently at each occurrence, selected from H, halogen,haloalkyl, NO₂, CO(C₁₋₄ alkyl), C₁₋₆ alkyl, OH, OMe, and CN.

In another embodiment, ring A is selected from

wherein R¹ is, independently at each occurrence, selected from H,halogen, and C₁₋₆ alkyl.

In another embodiment, ring A is

and is selected from

In another embodiment, ring A is

and is selected from

In another embodiment, ring A is

In yet another embodiment, the present invention provides compounds ofFormula (I), (II), or (III), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein ring B is selected from imidazole, oxadiazole, pyridine,pyridinone, pyridazine, pyridazinone, and phenyl.

In another embodiment,

is selected from

In another embodiment,

is selected from

In another embodiment,

is selected from

In still another embodiment,

is selected from

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment, ring C is a 4-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O.

In another embodiment, ring C is

wherein the nitrogen in the azetidine ring is attached to ring A.

In another embodiment, ring C is a 5-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O.

In another embodiment, ring C is

wherein W and Q are each independently selected from C, N, O, and S,whereby carbon is tetravalent, nitrogen is trivalent, and sulfur andoxygen are divalent; and

is a single or double bond.

In another embodiment, ring C is

wherein W and Q are each independently selected from N, NR⁹, CR², andCHR²;

In another embodiment, ring C is a 5-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O.

In another embodiment, ring C is

wherein U, V, W, and Q are each independently selected from the groupconsisting of C, N, O, and S, whereby carbon is tetravalent, nitrogen istrivalent, and sulfur and oxygen are divalent; and

is a single or double bond.

In another wherein U, V, W, and Q are each independently selected fromN, NR⁹, S, O, C, CR², and CHR².

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is

wherein W and Q are each independently selected from N, NR⁹, CR², andCHR²;

R^(2a) is selected from H, ═O, OH, NH₂, CF₃, halogen, and C₁₋₄ alkyloptionally substituted with OH.

In another embodiment, ring C is

wherein Q is selected from N and CR²;

R² is selected from H, NH₂, and C₁₋₄ alkyl substituted with OH.

In another embodiment, ring C is

In another embodiment, ring C is

W is selected from N and CR².

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is

In another embodiment, ring C is 6-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O.

In another embodiment, ring C is

In one embodiment, X^(1a) is selected from C₂₋₃ alkylene and C₂₋₄alkenylene; wherein said alkylene and alkenylene are optionallysubstituted with F, OH and C₁₋₄ alkyl; alternatively, one or two of thecarbon atoms of said alkylene and alkenylene may be replaced by O, NH,and N(C₁₋₄ alkyl).

In another embodiment, X^(1a) is selected from —CH₂CH₂—, —CHFCH₂—,—CH₂CHF—, —CH═CHCH₂—, —CH═C(C₁₋₄ alkyl)CH₂—, —C(C₁₋₄ alkyl)=CHCH₂—,—CH₂OCH₂—, —CH₂CH₂O—, —OCH₂CH₂—, —CH₂CF₂—, —(CH₂)₄CH(CF₃)—,—CH₂CH₂NHCO—, —CH₂NHCH₂—, —CH₂N(C₁₋₄ alkyl)CH₂—, —CH₂CONH—,—CH₂—CONH—CH₂—, and —CH₂—CON(C₁₋₄ alkyl).

In another embodiment, X^(1a) is selected from —CH₂CH₂—, —CH═CHCH₂—,—C(Me)=CHCH₂—, and —CH₂NHCH₂—.

In another embodiment, X^(1a) is selected from —CH₂CH₂—, —CH═CHCH₂—,—CHFCH₂—, and —CH₂CHF—.

In another embodiment, X^(1a) is selected from —CH₂CH₂— and —CH═CHCH₂—.

In another embodiment, X^(1a) is —CH₂CH₂—.

In one embodiment, X¹ is selected from C₁₋₃ alkylene and C₂₋₄alkenylene; wherein said alkylene and alkenylene are optionallysubstituted with OH and C₁₋₄ alkyl; alternatively, one or two of thecarbon atoms of said alkylene and alkenylene may be replaced by O,S(O)_(p), NH, N(C₁₋₄ alkyl), CONH, or CON(C₁₋₄ alkyl).

In another embodiment, X¹ is selected from —CH₂—, —CH(C₁₋₄ alkyl),—CH₂—CH₂—, —CH═CH—, —CH═C(C₁₋₄ alkyl)-, —C(C₁₋₄ alkyl)=CH—, —OCH₂—,—CH₂O—, —CF₂—, —(CH₂)₄CH(CF₃)—, —CH₂NHCO—, —CH₂NHCH₂—, —CH 2N(C₁₋₄alkyl)CH₂—, —CH₂CONH—, —CH₂—CONH—CH₂—, and —CH₂—CON(C₁₋₄ alkyl).

In another embodiment, X¹ is selected from —CH₂—, —CH═CH—, —C(Me)=CH—,—C≡C—, and —CH₂NH—.

In another embodiment, X¹ is selected from —CH₂—, —CH═CH—, and—C(Me)=CH—.

In another embodiment, X¹ is selected from —CH₂— and —CH═CH—.

In another embodiment, X¹ is —CH₂—.

In one embodiment, R¹ is, independently at each occurrence, selectedfrom H, halogen, NO₂, C₁₋₆ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), C₁₋₄alkylthio, OH, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, CN, and NH₂.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom H, halogen, NO₂, C₁₋₆ alkyl, OH, OMe, and CN.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom H and halogen.

In another embodiment, ring A is

wherein R^(1a) and R^(1b) are each independently selected from H andhalogen.

In another embodiment, R^(1a) is selected from H, F and Cl.

In another embodiment, R^(1a) is selected from H and F.

In another embodiment, R^(1a) is F and R^(1b) is Cl.

In another embodiment, R³ is selected from H, and C₁₋₄ alkyl.

In another embodiment, R³ is H.

In another embodiment, R⁴ is selected from H, C₁₋₄ alkyl, and hydroxyl.

In another embodiment, R⁴ is selected from H and C₁₋₄ alkyl.

In another embodiment, R⁴ is selected from H and methyl, ethyl,isopropyl, and C₃₋₆ cycloalkyl.

In another embodiment, R⁵ is selected from H and C₁₋₄ alkyl.

In another embodiment, R⁵ is selected from H and methyl.

In another embodiment, R⁶ is selected from H, halogen, haloalkyl,C(O)OH, C(O)O—R^(a), C(O)NR^(b)R^(c), wherein:

R^(a) is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, 5- to 6-memberedheteroaryl, 4- to 7-membered heterocycle, and benzyl, said groups beingoptionally substituted with OH, OMe, and halogen;

R^(b) is selected from H and C₁₋₆ alkyl;

R^(c) is selected from H and C₁₋₆ alkyl;

alternatively, R^(b) and R^(c) are taken together with the nitrogen atomto which they are attached to form a 4- to 7-membered heterocycleoptionally substituted with OH, OMe, and halogen.

In another embodiment, R⁶ is selected from H, halogen, C(O)OH, andC(O)O(C₁₋₄ alkyl).

In another embodiment, R⁷ is selected from H, C₁₋₄ alkyl, and CF₃.

In another embodiment, R⁶ and R⁷ are taken together to be ═O.

In another embodiment, R⁸ is selected from H, halogen, haloalkyl, CN,OH, NR¹²R¹², —CH₂NH₂, C(O)OH, —(CH₂)_(n)—NHC(O)OR¹², —NHC(O)R¹²,—NHC(O)NR¹²R¹², —NHS(O)₂C₁₋₄ alkyl, —(CH₂)_(n)—CONR¹²R¹²,—(CH₂)_(n)C(O)O(C₁₋₄ alkyl), —(CH₂)_(n)—C₃₋₁₀ carbocycle, and—(CH₂)_(n)-4-10-membered heterocycle wherein said carbocycle andheterocycle are optionally substituted with R¹³.

In another embodiment, R⁸ is selected from H, CN, OH, NR¹²R¹², C(O)OH,—(CH₂)_(n)—NHC(O)OR¹², —NHS(O)₂C₁₋₄ alkyl, —(CH₂)_(n)—CONR¹²R¹²,—(CH₂)_(n)C(O)O(C₁₋₄ alkyl), —(CH₂)_(n)—C₃₋₁₀ carbocycle, and—(CH₂)_(n)-4-10-membered heterocycle optionally substituted with R¹³.

In another embodiment, R⁸ is selected from H, NR¹²R¹², C(O)OH, andNHC(O)O—C₁₋₄ alkyl.

In another embodiment, R⁸ is NH₂, C(O)OH, and NHC(O)OR¹².

In another embodiment, R¹² is selected from H, C₁₋₄ alkyl (optionallysubstituted with halogen, hydroxy, alkoxy, carboxy, alkoxycarbonyl),—(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4-10-membered heterocycle,wherein said carbocycle and heterocycle are optionally substituted withR¹³.

In another embodiment, R¹² is selected from H, C₁₋₄ alkyl (optionallysubstituted with F, OH, —O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)),—(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4-10-membered heterocycle,wherein said carbocycle and heterocycle are optionally substituted withR¹³.

In another embodiment, R¹² is selected from methyl, —(CH₂)_(n)—OC₁₋₄alkyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—C₃₋₆ cycloalkyl, and—(CH₂)^(n)-5-membered heterocycle optionally substituted with R¹³ andselected from

R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O.

In another embodiment, R⁸ is selected from H, halogen, NHC(O)O—C₁₋₄alkyl, CN, OH, O—C₁₋₄ alkyl; CF₃, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H,—(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂,—NHCO(C₁₋₄ alkyl), —NHCO₂(CH₂)₁₋₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₁₋₃O(C₁₋₄alkyl), NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₁₋₂OH,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, NHC(O)NH(C₁₋₄ alkyl)N[5- to 6-memberedheterocycle)], —NHSO₂(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, and —CH₂CONH₂.

In another embodiment, R⁸ is selected from H, halogen, NHC(O)O—C₁₋₄alkyl, NHC(O)(CH₂)₂OMe, CN, OH, and O—C₁₋₄ alkyl.

In another embodiment, R⁸ is NHC(O)O—C₁₋₄ alkyl.

In another embodiment, the present invention provides compounds ofFormula (I), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

ring A is a 6-membered aryl or piperidine, said ring moieties areoptionally substituted with R¹;

ring B is selected from imidazole, oxadiazole, pyridine, pyridinone,pyridazine, pyridazinone, pyrimidine, and phenyl, said ring moieties areoptionally substituted with R¹⁰; and

ring C is selected from imidazole, pyrazole, pyrrole, and triazole, saidring moieties are optionally substituted with R².

In one embodiment, the present invention provides compounds of Formula(VII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring B is a 5- to 6-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NH, S(O)_(p), and O, wherein saidheterocycle are optionally substituted with one or more R¹⁰ as valenceallows;

ring C is a 4- to 5-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NR⁹, S(O)_(p), and O, wherein saidheterocycle are optionally substituted with one or more R² as valenceallows;

X¹ is selected from C₁₋₄ alkylene, and C₂₋₄ alkenylene wherein saidalkylene and alkenylene are optionally substituted with OH and C₁₋₄alkyl; alternatively one or more of the carbon atoms of said alkyleneand alkenylene may be replaced by O, S(O)_(p), NH, and N(C₁₋₄ alkyl);

R^(1a) and R^(1b) are each independently selected from H and halogen;

R² is selected from H, ═O, OH, NH₂, CF₃, halogen, and C₁₋₄ alkyloptionally substituted with OH;

R³ is selected from H and C₁₋₄ alkyl;

alternatively, R² and R³, together with the atoms to which they aredirectly or indirectly attached, form a ring wherein said ring isoptionally substituted with ═O;

R⁴ is selected from H, C₁₋₄ alkyl, hydroxyl, and C₃₋₆ cycloalkyl;

R⁵ is selected from H and C₁₋₄ alkyl;

R⁶ is selected from H, halogen, haloalkyl, C(O)OH, C(O)O—R¹¹, andC(O)NR¹²R¹³;

R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;

alternatively, R⁶ and R⁷ together are ═O;

R⁸ is selected from H, halogen, NHC(O)O—C₁₋₄ alkyl, CN, OH, O—C₁₋₄alkyl; CF₃, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl),—NHCO₂(CH₂)₁₋₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₁₋₃O(C₁₋₄ alkyl),NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₁₋₂OH, —NHCO₂CH₂CO₂H,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,NHC(O)NH(C₁₋₄ alkyl)N[5- to 6-membered heterocycle)], —NHSO₂(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, and —CH₂CONH₂;

R⁹ is selected from H and C₁₋₄ alkyl;

R¹⁰ is, independently at each occurrence, selected from H, halogen, CN,OH, ═O, NH₂, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, CF₃, CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), and CONH;

R¹¹ is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, 5- to 6-memberedheteroaryl, 4- to 7-membered heterocycle, and benzyl, said groups beingoptionally substituted with OH, OMe, and halogen;

R¹² is selected from H and C₁₋₆ alkyl;

R¹³ is selected from H and C₁₋₆ alkyl;

alternatively, R¹² and R¹³ are taken together with the nitrogen atom towhich they are attached to form a 4- to 7-membered heterocycle,optionally substituted with OH, OMe, and halogen; and

p is, independently at each occurrence, selected from 0, 1, and 2.

In another embodiment, the present invention provides compounds ofFormula (VII), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

is selected from

ring C is

R² is selected from H and NH₂; and

R⁴ is selected from H, methyl, and ethyl; and

R⁶ and R⁷ together are ═O; and

R⁸ is NHC(O)O—C₁₋₄ alkyl.

In another embodiment, the present invention provides compounds ofFormula (VIII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein the variables have the meaningsas defined in Formula (VII).

In another embodiment, the present invention provides compounds ofFormula (IX):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein the variables have the meaningsas defined in Formula (VII).

In another embodiment, the present invention provides compounds ofFormula (IXa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein the variables have the meaningsas defined in Formula (IVa).

In another embodiment, the present invention provides compounds ofFormula (X):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein the variables have the meaningsas defined in Formula (VII).

In another embodiment, the present invention provides compounds ofFormula (XI):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein the variables have the meaningsas defined in Formula (VII).

In another embodiment, the present invention provides compounds ofFormula (XIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein the variables have the meaningsas defined in Formula (IVa).

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds exemplified in the presentapplication.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦10 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦1 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦0.5 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦0.1 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are clopidogrel and/or aspirin, or a combinationthereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a thromboembolic disorder comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy for thetreatment and/or prophylaxis of a thromboembolic disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, for themanufacture of a medicament for the treatment and/or prophylaxis of athromboembolic disorder.

In another embodiment, the present invention provides a method fortreatment and/or prophylaxis of a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a first and second therapeutic agent, wherein the firsttherapeutic agent is a compound of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, and the second therapeutic agent is at least one agentselected from a second factor Xa inhibitor, an anti-coagulant agent, ananti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent,and a fibrinolytic agent. Preferably, the second therapeutic agent is atleast one agent selected from warfarin, unfractionated heparin, lowmolecular weight heparin, synthetic Pentasaccharide, hirudin,argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin,mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam,ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,melagatran, disulfatohirudin, tissue plasminogen activator, modifiedtissue plasminogen activator, anistreplase, urokinase, andstreptokinase. Preferably, the second therapeutic agent is at least oneanti-platelet agent. Preferably, the anti-platelet agent(s) areclopidogrel and/or aspirin, or a combination thereof.

The thromboembolic disorder includes arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders. Examples of the thromboembolicdisorder include, but are not limited to, unstable angina, an acutecoronary syndrome, atrial fibrillation, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from medical implants, devices, or procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of an inflammatory disorder comprising:administering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Examples of the inflammatorydisorder include, but are not limited to, sepsis, acute respiratorydistress syndrome, and systemic inflammatory response syndrome.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intreatment and/or prophylaxis of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro (F), chloro (Cl), bromo (Br), andiodo (I). “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogens.Examples of haloalkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl,pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, andheptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” thatis intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more fluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “carboxy” refers to the group —C(═O)OH.

The term “alkoxycarbonyl” refers to the group —C(═O)OR^(w) where R^(w)is an alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridgedrings are also included in the definition of carbocycle (e.g.,[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers to phenyland naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀ aryl” or“C₆₋₁₀ aryl” or “aromatic residue” may be unsubstituted or substitutedwith 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃, Cl, F, Br, I,CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃,S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “arylalkyloxy” refers to an arylalkyl bonded through an oxygenlinkage (—O-arylalkyl).

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)p, wherein pis 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. Examples of a bicyclic heterocyclic group are, but notlimited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of Formula (I) may have prodrug forms. Anycompound that will be converted in vivo to provide the bioactive agent(i.e., a compound of Formula (I)) is a prodrug within the scope andspirit of the invention. Various forms of prodrugs are well known in theart. For examples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆ alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆ alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl), C₁₋₆ alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “saturated” for saturated, “MW” for molecularweight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me Methyl-   Et Ethyl-   Pr Propyl-   i-Pr Isopropyl-   Bu Butyl-   i-Bu Isobutyl-   t-Bu tert-butyl-   Ph Phenyl-   Bn Benzyl-   Boc tert-butyloxycarbonyl-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN Azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   CBz Carbobenzyloxy-   CH₂Cl₂ Dichloromethane-   CH₃CN or ACN Acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ Chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DCM dichloromethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs (II)    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂SO₄ sulfuric acid-   K₂CO₃ potassium carbonate-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS polystyrene-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T₃P propane phosphonic acid anhydride-   TRIS tris(hydroxymethyl)aminomethane

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis.

IV. Biology

While blood coagulation is essential to the regulation of an organism'shemostasis, it is also involved in many pathological conditions. Inthrombosis, a blood clot, or thrombus, may form and obstruct circulationlocally, causing ischemia and organ damage. Alternatively, in a processknown as embolism, the clot may dislodge and subsequently become trappedin a distal vessel, where it again causes ischemia and organ damage.Diseases arising from pathological thrombus formation are collectivelyreferred to as thromboembolic disorders and include acute coronarysyndrome, unstable angina, myocardial infarction, thrombosis in thecavity of the heart, ischemic stroke, deep vein thrombosis, peripheralocclusive arterial disease, transient ischemic attack, and pulmonaryembolism. In addition, thrombosis occurs on artificial surfaces incontact with blood, including catheters, stents, artificial heartvalves, and hemodialysis membranes.

Some conditions contribute to the risk of developing thrombosis. Forexample, alterations of the vessel wall, changes in the flow of blood,and alterations in the composition of the vascular compartment. Theserisk factors are collectively known as Virchow's triad. (Colman, R. W.et al., eds., Hemostasis and Thrombosis, Basic Principles and ClinicalPractice, 5th Edition, p. 853, Lippincott Williams & Wilkins (2006))

Antithrombotic agents are frequently given to patients at risk ofdeveloping thromboembolic disease because of the presence of one or morepredisposing risk factors from Virchow's triad to prevent formation ofan occlusive thrombus (primary prevention). For example, in anorthopedic surgery setting (e.g., hip and knee replacement), anantithrombotic agent is frequently administered prior to a surgicalprocedure. The antithrombotic agent counterbalances the prothromboticstimulus exerted by vascular flow alterations (stasis), potentialsurgical vessel wall injury, as well as changes in the composition ofthe blood due to the acute phase response related to surgery. Anotherexample of the use of an antithrombotic agent for primary prevention isdosing with aspirin, a platelet activation inhibitor, in patients atrisk for developing thrombotic cardiovascular disease. Well recognizedrisk factors in this setting include age, male gender, hypertension,diabetes mellitus, lipid alterations, and obesity.

Antithrombotic agents are also indicated for secondary prevention,following an initial thrombotic episode. For example, patients withmutations in factor V (also known as factor V Leiden) and additionalrisk factors (e.g., pregnancy), are dosed with anticoagulants to preventthe reoccurrence of venous thrombosis. Another example entails secondaryprevention of cardiovascular events in patients with a history of acutemyocardial infarction or acute coronary syndrome. In a clinical setting,a combination of aspirin and clopidogrel (or other thienopyridines) maybe used to prevent a second thrombotic event.

Antithrombotic agents are also given to treat the disease state (i.e.,by arresting its development) after it has already started. For example,patients presenting with deep vein thrombosis are treated withanticoagulants (i.e., heparin, warfarin, or LMWH) to prevent furthergrowth of the venous occlusion. Over time, these agents also cause aregression of the disease state because the balance betweenprothrombotic factors and anticoagulant/profibrinolytic pathways ischanged in favor of the latter. Examples on the arterial vascular bedinclude the treatment of patients with acute myocardial infarction oracute coronary syndrome with aspirin and clopidogrel to prevent furthergrowth of vascular occlusions and eventually leading to a regression ofthrombotic occlusions.

Thus, antithrombotic agents are used widely for primary and secondaryprevention (i.e., prophylaxis or risk reduction) of thromboembolicdisorders, as well as treatment of an already existing thromboticprocess. Drugs that inhibit blood coagulation, or anticoagulants, are“pivotal agents for prevention and treatment of thromboembolicdisorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, “on-pump”cardiovascular surgery, vessel grafts, bacterial sepsis), on cellsurfaces, cellular receptors, cell debris, DNA, RNA, and extracellularmatrices. This process is also termed contact activation. Surfaceabsorption of factor XII leads to a conformational change in the factorXII molecule, thereby facilitating activation to proteolytic activefactor XII molecules (factor XIIa and factor XIIf). Factor XIIa (orXIIf) has a number of target proteins, including plasma prekallikreinand factor XI. Active plasma kallikrein further activates factor XII,leading to an amplification of contact activation. Alternatively, theserine protease prolylcarboxylpeptidase can activate plasma kallikreincomplexed with high molecular weight kininogen in a multiprotein complexformed on the surface of cells and matrices (Shariat-Madar et al.,Blood, 108:192-199 (2006)). Contact activation is a surface mediatedprocess responsible in part for the regulation of thrombosis andinflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R., “Contact Activation Pathway”, Hemostasis andThrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier,A. H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128(1998)). The biological relevance of the contact activation system forthromboembolic diseases is supported by the phenotype of factor XIIdeficient mice. More specifically, factor XII deficient mice wereprotected from thrombotic vascular occlusion in several thrombosismodels as well as stroke models and the phenotype of the XII deficientmice was identical to XI deficient mice (Renne et al., J. Exp. Med.,202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518(2006)). The fact that factor XI is down-stream from factor XIIa,combined with the identical phenotype of the XII and XI deficient micesuggest that the contact activation system could play a major role infactor XI activation in vivo.

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-I370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H413, D464, and S557). Activation offactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated factor XI. After activation, factor XIa remains surface boundand recognizes factor IX as its normal macromolecular substrate.(Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000))

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal., Thromb. Res., 101:329-354 (2001).) Thus, inhibitors of factor XIaare expected to be anticoagulant and profibrinolytic.

Further evidence for the anti-thromboembolic effects of targeting factorXI is derived from mice deficient in factor XI. It has been demonstratedthat complete fXI deficiency protected mice from ferric chloride(FeCl₃)-induced carotid artery thrombosis (Rosen et al., Thromb.Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost., 3:695-702(2005)). Also, factor XI deficiency rescues the perinatal lethalphenotype of complete protein C deficiency (Chan et al., Amer. J.Pathology, 158:469-479 (2001)). Furthermore, baboon cross-reactive,function blocking antibodies to human factor XI protect against baboonarterial-venous shunt thrombosis (Gruber et al., Blood, 102:953-955(2003)). Evidence for an antithrombotic effect of small moleculeinhibitors of factor XIa is also disclosed in published U.S. PatentApplication No. 2004/0180855 A1. Taken together, these studies suggestthat targeting factor XI will reduce the propensity for thrombotic andthromboembolic diseases.

Genetic evidence indicates that factor XI is not required for normalhomeostasis, implying a superior safety profile of the factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (factor VIII deficiency) or hemophilia B (factor IXdeficiency), mutations of the factor XI gene causing factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g., oral cavity, and urogenital system). The majority of the casesare fortuitously identified by preoperative prolongation of aPTT(intrinsic system) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The aPTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates. (Gailani,D., Frontiers in Bioscience, 6:201-207 (2001); Gailani, D. et al., BloodCoagulation and Fibrinolysis, 8:134-144 (1997).) Taken together, theseobservations suggest that high levels of inhibition of factor XIa shouldbe well tolerated. This is in contrast to gene targeting experimentswith other coagulation factors, excluding factor XII.

In vivo activation of factor XI can be determined by complex formationwith either C1 inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, factor XI activation contributes tothrombin formation (Minnema, M. C. et al., Arterioscler. Thromb. Vasc.Biol., 20:2489-2493 (2000)). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and factorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In anotherstudy, Factor XI levels above the 90th percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al., N. Engl. J. Med., 342:696-701 (2000)).

Plasma kallikrein is a zymogen of a trypsin-like serine protease and ispresent in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of factor XI. Overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Proteolytic activation by factor XIIa atan internal I 389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of plasma kallikrein iscontained in the light chain. The light chain of plasma kallikreinreacts with protease inhibitors, including alpha 2 macroglobulin andC1-inhibitor. Interestingly, heparin significantly accelerates theinhibition of plasma kallikrein by antithrombin III in the presence ofhigh molecular weight kininogen (HMWK). In blood, the majority of plasmakallikrein circulates in complex with HMWK. Plasma kallikrein cleavesHMWK to liberate bradykinin. Bradykinin release results in increase ofvascular permeability and vasodilation (for review, Coleman, R.,“Contact Activation Pathway”, Hemostasis and Thrombosis, pp. 103-122,Lippincott Williams & Wilkins (2001); Schmaier A. H., “ContactActivation”, Thrombosis and Hemorrhage, pp. 105-128 (1998)).

Also, it is preferred to find new compounds with improved activity in invitro clotting assays, compared with known serine protease inhibitors,such as the activated partial thromboplastin time (aPTT) or prothrombintime (PT) assay. (for a description of the aPTT and PT assays see,Goodnight, S. H. et al., “Screening Tests of Hemostasis”, Disorders ofThrombosis and Hemostasis: A Clinical Guide, 2nd Edition, pp. 41-51,McGraw-Hill, New York (2001)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known serine proteaseinhibitors, in one or more of the following categories that are given asexamples, and are not intended to be limiting: (a) pharmacokineticproperties, including oral bioavailability, half life, and clearance;(b) pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the enzyme; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects,including selectivity versus other biological targets; and (h) factorsthat improve manufacturing costs or feasibility.

Pre-clinical studies demonstrated significant antithrombotic effects ofsmall molecule factor XIa inhibitors in rabbit and rat model of arterialthrombosis, at doses that preserved hemostasis. (Wong P. C. et al.,American Heart Association Scientific Sessions, Abstract No. 6118, Nov.12-15, 2006; Schumacher, W. et al., Journal of Thrombosis andHaemostasis, 3(Suppl. 1):P 1228 (2005); Schumacher, W. A. et al.,European Journal of Pharmacology, pp. 167-174 (2007)). Furthermore, itwas observed that in vitro prolongation of the aPTT by specific XIainhibitors is a good predictor of efficacy in our thrombosis models.Thus, the in vitro aPTT test can be used as a surrogate for efficacy invivo.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor XIa and/or plasma kallikreinand/or to prevent or treat the disorders listed herein. When applied toa combination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi); clotting within a blood vessel that maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to are family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Risk factors for congenital thrombophilia include gain of functionmutations in coagulation factors or loss of function mutations in theanticoagulant- or fibrinolytic pathways.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N Engl. J.Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA, 293(6):715-722(2005)). Hence, the most common cancers associated with thrombosis inmen are prostate, colorectal, brain, and lung cancer, and in women arebreast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular heparin preparations have been approved by theFDA for these indications.

There are three main clinical situations when considering the preventionof VTE in a medical cancer patient: (i) the patient is bedridden forprolonged periods of time; (ii) the ambulatory patient is receivingchemotherapy or radiation; and (iii) the patient is with indwellingcentral vein catheters. Unfractionated heparin (UFH) and low molecularweight heparin (LMWH) are effective antithrombotic agents in cancerpatients undergoing surgery. (Mismetti, P. et al., British Journal ofSurgery, 88:913-930 (2001).)

A. In Vitro Assays

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation Factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikrein orthrombin, can be determined using a relevant purified serine protease,respectively, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Assays were conducted at roomtemperature or at 37° C. Hydrolysis of the substrate resulted in therelease of pNA (para nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nm, or the release of AMC (amino methylcoumarin), which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nmwith excitation at 380 nm. A decrease in the rate of absorbance orfluorescence change in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 25-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.001 M.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.1% PEG 8000 at a pH of7.5. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 0.5-10 nM, recombinantsoluble tissue factor at a concentration of 10-40 nM and the syntheticsubstrate H-D-Ile-Pro-Arg-pNA (S-2288; CHROMOGENIX® or BMPM-2; AnaSpec)at a concentration of 0.001-0.0075 M.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.0000001 M Refludan (Berlex), 0.05 M TRIS base and0.5% PEG 8000 at a pH of 7.4. Refludan was added to inhibit smallamounts of thrombin in the commercial preparations of human Factor IXa.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;CHROMOGENIX®) at a concentration of 0.0002-0.00035 M.

Factor XIIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000. Determinations weremade using purified human Factor XIIa at a final concentration of 4 nM(American Diagnostica) and the synthetic substrate SPECTROZYME® #312(H-D-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica) at a concentrationof 0.00015 M.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human kallikrein (EnzymeResearch Laboratories) at a final assay concentration of 200 pM and thesynthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; CHROMOGENIX®) at aconcentration of 0.00008-0.0004 M.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.0004 M.

The Michaelis constant, K_(m), for substrate hydrolysis by eachprotease, was determined at 25° C. or 37° C. Values of K_(i) weredetermined by allowing the protease to react with the substrate in thepresence of the inhibitor. Reactions were allowed to go for periods of20-180 minutes (depending on the protease) and the velocities (rate ofabsorbance or fluorescence change versus time) were measured. Thefollowing relationships were used to calculate K_(i) values:

(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))

for a competitive inhibitor with one binding site; or

v _(s) /v _(o) =A+((B−A)/(1+((IC ₅₀/(I))^(n))));

and

K _(i) =IC ₅₀/(1+S/K _(m))

for a competitive inhibitor,

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually locked at zero);

B is the maximum activity remaining (usually locked at 1.0);

n is the Hill coefficient, a measure of the number and cooperativity ofpotential inhibitor binding sites;

IC₅₀ is the concentration of inhibitor that produces 50% inhibitionunder the assay conditions;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate; and

K_(m) is the Michaelis constant for the substrate.

The selectivity of a compound may be evaluated by taking the ratio ofthe K_(i) value for a given protease with the K_(i) value for theprotease of interest (i.e., selectivity for FXIa versus protease P=K_(i)for protease P/K_(i) for FXIa). Compounds with selectivity ratios >20are considered selective. Compounds with selectivity ratios >100 arepreferred, and compounds with selectivity ratios >500 are morepreferred.

The effectiveness of compounds of the present invention as inhibitors ofcoagulation can be determined using a standard or modified clottingassay. An increase in the plasma clotting time in the presence ofinhibitor is indicative of anticoagulation. Relative clotting time isthe clotting time in the presence of an inhibitor divided by theclotting time in the absence of an inhibitor. The results of this assaymay be expressed as IC1.5× or IC2×, the inhibitor concentration requiredto increase the clotting time by 50 or 100 percent, respectively. TheIC1.5× or IC2× is found by linear interpolation from relative clottingtime versus inhibitor concentration plots using inhibitor concentrationthat spans the IC1.5× or IC2×.

Clotting times are determined using citrated normal human plasma as wellas plasma obtained from a number of laboratory animal species (e.g.,rat, or rabbit). A compound is diluted into plasma beginning with a 10mM DMSO stock solution. The final concentration of DMSO is less than 2%.Plasma clotting assays are performed in an automated coagulationanalyzer (Sysmex, Dade-Behring, Ill.). Similarly, clotting times can bedetermined from laboratory animal species or humans dosed with compoundsof the invention.

Activated Partial Thromboplastin Time (aPTT) is determined using ALEXIN®(Trinity Biotech, Ireland) or ACTIN® (Dade-Behring, Ill.) following thedirections in the package insert. Plasma (0.05 mL) is warmed to 37° C.for 1 minute. ALEXIN® or ACTIN® (0.05 mL) is added to the plasma andincubated for an additional 2 to 5 minutes. Calcium chloride (25 mM,0.05 mL) is added to the reaction to initiate coagulation. The clottingtime is the time in seconds from the moment calcium chloride is addeduntil a clot is detected.

Prothrombin Time (PT) is determined using thromboplastin (ThromboplastinC Plus or INNOVIN®, Dade-Behring, Ill.) following the directions in thepackage insert. Plasma (0.05 mL) is warmed to 37° C. for 1 minute.Thromboplastin (0.1 mL) is added to the plasma to initiate coagulation.The clotting time is the time in seconds from the moment thromboplastinis added until a clot is detected.

The exemplified Examples disclosed below were tested in the Factor XIaassay described above and found having Factor XIa inhibitory activity. Arange of Factor XIa inhibitory activity (Ki values) of ≦10 μM (10000 nM)was observed. Table 1 below lists Factor XIa Ki values measured for thefollowing examples.

TABLE 1 Example No. Factor XIa Ki (nM) 3 <5.00 5 5.52 11 69.44 15 <5.0018 98.71 21 9.08 24 <5.00 26 177.50 32 11.43 39 10.82 40 <5.00 41 12.7752 216.90 58 934.60 71 32.83 72 10.38 75 36.48 78 <5.00 88 52.61 113<5.00 120 <5.00 127 <5.00 131 <5.00 133 <5.00 134 <5.00 137 546.60 1395.49 151 17.26 156 16.81 158 <5.00 159 9.94 165 5079.00 177 54.93 1906.65 193 2983.00 207 153.00 221 311.60 227 <5.00 232 4287.00 234 <5.00246 <5.00 251 <5.00 256 <5.00 257 <5.00 262 13.61 263 33.25

B. In Vivo Assays

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arterio-venous Shunt ThrombosisModels.

a. In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT) Model

The rabbit ECAT model, described by Wong et al. (J. Pharmacol. Exp.Ther., 295:212-218 (2000)), can be used in this study. Male New ZealandWhite rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM)and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics aresupplemented as needed. An electromagnetic flow probe is placed on asegment of an isolated carotid artery to monitor blood flow. Test agentsor vehicle will be given (i.v., i.p., s.c., or orally) prior to or afterthe initiation of thrombosis. Drug treatment prior to initiation ofthrombosis is used to model the ability of test agents to prevent andreduce the risk of thrombus formation, whereas dosing after initiationis used to model the ability to treat existing thrombotic disease.Thrombus formation is induced by electrical stimulation of the carotidartery for 3 min at 4 mA using an external stainless-steel bipolarelectrode. Carotid blood flow is measured continuously over a 90-minperiod to monitor thrombus-induced occlusion. Total carotid blood flowover 90 min is calculated by the trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid Em. equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

b. In Vivo Rabbit Arterio-Venous (AV) Shunt Thrombosis Model

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.,J. Pharmacol. Exp. Ther. 292:351-357 (2000)), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed. The femoral artery, jugular veinand femoral vein are isolated and catheterized. A saline-filled AV shuntdevice is connected between the femoral arterial and the femoral venouscannulae. The AV shunt device consists of an outer piece of tygon tubing(length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing(length=2.5 cm; internal diameter=4.8 mm) The AV shunt also contains an8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows fromthe femoral artery via the AV-shunt into the femoral vein. The exposureof flowing blood to a silk thread induces the formation of a significantthrombus. Forty minutes later, the shunt is disconnected and the silkthread covered with thrombus is weighed. Test agents or vehicle will begiven (i.v., i.p., s.c., or orally) prior to the opening of the AVshunt. The percentage inhibition of thrombus formation is determined foreach treatment group. The ID₅₀ values (dose that produces 50% inhibitionof thrombus formation) are estimated by a nonlinear least squareregression program using the Hill sigmoid Em. equation (DeltaGraph; SPSSInc., Chicago, Ill.).

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using C1-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue dye is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, factor XII, factor XI, high molecularweight kininogen, C1-esterase inhibitors).

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfate, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 toabout 100 milligrams of the compound of the present invention and about0.1 to about 100 milligrams per kilogram of patient body weight. For atablet dosage form, the compounds of this invention generally may bepresent in an amount of about 5 to about 100 milligrams per dosage unit,and the second anti-coagulant in an amount of about 1 to about 50milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to about 25 milligrams of thecompound of the present invention and about 50 to about 150 milligramsof the anti-platelet agent, preferably about 0.1 to about 1 milligramsof the compound of the present invention and about 1 to about 3milligrams of anti-platelet agents, per kilogram of patient body weight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to about 1 milligrams of the compound of the presentinvention, per kilogram of patient body weight and, in the case of thethrombolytic agents, the usual dosage of the thrombolytic agent whenadministered alone may be reduced by about 50-80% when administered witha compound of the present invention.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, potassium channel blockers, calciumchannel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmicagents, antiatherosclerotic agents, anticoagulants, antithromboticagents, prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an antiarrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic Pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition wherein the additional therapeutic agent is anantihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, renin inhibitors(alliskerin) and vasopepsidase inhibitors, an antiarrythmic agentselected from IKur inhibitors, an anticoagulant selected from thrombininhibitors, antithrombin-III activators, heparin co-factor IIactivators, other factor XIa inhibitors, other kallikrein inhibitors,plasminogen activator inhibitor (PAI-1) antagonists, thrombinactivatable fibrinolysis inhibitor (TAFI) inhibitors, factor VIIainhibitors, factor IXa inhibitors, and factor Xa inhibitors, or anantiplatelet agent selected from GPIIb/IIIa blockers, GP Ib/IX blockers,protease activated receptor 1 (PAR-1) antagonists, protease activatedreceptor4 (PAR-4) antagonists, prostaglandin E2 receptor EP3antagonists, collagen receptor antagonists, phosphodiesterase-IIIinhibitors, P2Y₁ receptor antagonists, P2Y₁₂ antagonists, thromboxanereceptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or acombination thereof.

In another embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent is theanti-platelet agent clopidogrel.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds that can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX®), syntheticPentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other factor VIIa inhibitors, factor IXainhibitors, factor Xa inhibitors (e.g., ARIXTRA®, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granule-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDs) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDs,aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Othersuitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g.,E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), andpharmaceutically acceptable salts or prodrugs thereof.

Other examples of suitable anti-platelet agents for use in combinationwith the compounds of the present invention, with or without aspirin,are ADP (adenosine diphosphate) receptor antagonists, preferablyantagonists of the purinergic receptors P2Y₁ and P2Y₁₂, with P2Y₁₂ beingeven more preferred. Preferred P2Y₁₂ receptor antagonists includeclopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, andpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine andclopidogrel are also preferred compounds since they are known to be moregentle than aspirin on the gastro-intestinal tract in use. Clopidogrelis an even more preferred agent.

A preferred example is a triple combination of a compound of the presentinvention, aspirin, and another anti-platelet agent. Preferably, theanti-platelet agent is clopidogrel or prasugrel, more preferablyclopidogrel.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including serotonin)and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, andthose disclosed in WO 98/37075 and WO 02/044145, and pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, andother statins), low-density lipoprotein (LDL) receptor activitymodulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants(e.g., cholestyramine and colestipol), nicotinic acid or derivativesthereof (e.g., NIASPAN®), GPR109B (nicotinic acid receptor) modulators,fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrateand benzafibrate) and other peroxisome proliferator-activated receptors(PPAR) alpha modulators, PPARdelta modulators (e.g., GW-501516),PPARgamma modulators (e.g., rosiglitazone), compounds that have multiplefunctionality for modulating the activities of various combinations ofPPARalpha, PPARgamma and PPARdelta, probucol or derivatives thereof(e.g., AGI-1067), cholesterol absorption inhibitors and/or Niemann-PickC1-like transporter inhibitors (e.g., ezetimibe), cholesterol estertransfer protein inhibitors (e.g., CP-529414), squalene synthaseinhibitors and/or squalene epoxidase inhibitors or mixtures thereof,acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2inhibitors, dual ACAT1/2 inhibitors, ileal bile acid transportinhibitors (or apical sodium co-dependent bile acid transportinhibitors), microsomal triglyceride transfer protein inhibitors,liver-X-receptor (LXR) alpha modulators, LXRbeta modulators, LXR dualalpha/beta modulators, FXR modulators, omega 3 fatty acids (e.g.,3-PUFA), plant stanols and/or fatty acid esters of plant stanols (e.g.,sitostanol ester used in BENECOL® margarine), endothelial lipaseinhibitors, and HDL functional mimetics which activate reversecholesterol transport (e.g., apoAI derivatives or apoAI peptidemimetics).

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimenter that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent and selective Factor XIa inhibitor of the presentinvention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

VI. General Synthesis Including Schemes

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry(Maffrand, J. P. et al., Heterocycles, 16(1):35-37 (1981)). Generalsynthetic schemes for preparing compounds of the present invention aredescribed below. These schemes are illustrative and are not meant tolimit the possible techniques one skilled in the art may use to preparethe compounds disclosed herein. Different methods to prepare thecompounds of the present invention will be evident to those skilled inthe art. Additionally, the various steps in the synthesis may beperformed in an alternate sequence in order to give the desired compoundor compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Example compounds are typicallyprepared as racemic mixtures. Preparation of homochiral examples may becarried out by techniques known to one skilled in the art. For example,homochiral compounds may be prepared by separation of racemic productsby chiral phase preparative HPLC. Alternatively, the example compoundsmay be prepared by methods known to give enantiomerically enrichedproducts. These include, but are not limited to, the incorporation ofchiral auxiliary functionalities into racemic intermediates which serveto control the diastereoselectivity of transformations, providingenantio-enriched products upon cleavage of the chiral auxiliary.

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,4th Edition, Wiley-Interscience (2006)).

Certain 2-bromoacetophenone analogs (1b) that are not commerciallyavailable but used in the current invention may be synthesized fromcommercially available starting materials as described in Scheme 1.Acetophenone derivatives 1a can be treated with a brominating reagentsuch as bromine in a solvent such as CHCl₃ to give 1b. Alternatively,acetophenone derivatives 1a can be treated with either copper (II)bromide in a solvent such as EtOAc at elevated temperature orphenyltrimethylammonium tribromide in a solvent such as THF at lowtemperature to provide 1b. Benzoic acid derivatives 1c can be treatedsequentially with oxalyl chloride in a suitable solvent, such as DCM,containing a few drops of DMF, and then treated withtrimethylsilyldiazomethane in a suitable solvent or solvent combination,such as ACN and hexane. The intermediate diazoketone is isolated andtreated with aqueous hydrobromic acid and DCM to provide 1b.Alternatively the benzoic acid derivatives 1c can be converted to theacetophenone derivatives 1a in three steps as described in Scheme 1.Alternatively, Stille coupling between a suitably substituted arylhalide or triflate and tributyl-(1-ethoxyvinyl) stannane with apalladium catalyst, such as bis-(triphenylphosphine)palladiumdichloride, in a suitable solvent, such as toluene, at elevatedtemperature yields the enol ether 1e, which can then be converted to 1bwith N-bromosuccinimide.

Triazole acids of this invention such as 2c, 2d, 2e, 2f can be easilyprepared from readily accessible anilines in a three step processoutlined in Scheme 2. Formation of the arylazide (2b) intermediate viadiazotization and displacement with sodium azide followed bycondensation with appropriate acetylenic compounds and removal of theprotecting groups known to those in the art should afford intermediatessuch as 2c. Condensation of the arylazides with either malonates orketoesters followed by hydrolysis should afford intermediates of thisinvention such as 2d, 2e and 2f. In cases wherein the anilines are notavailable, the corresponding arylcarboxylic acids can be used which arethen converted to the anilines via the Curtius rearrangement.Alternatively haloaryl intermediates can be lithiated via BuLi andreacted with CO₂ to afford the corresponding carboxylic acids which canthen be converted to the anilines as outlined below.

Substituted hydrazine (3a) of this invention can be obtained fromcommercial sources or can be made from the corresponding anilines viadiazotization followed by reduction with tin chloride. These can bereacted either directly or after isolation with an appropriatemalononitrile to afford aminopyrazole such as compound 3b. Treatment of3b with isoamylnitrite in THF under elevated temperatures should providethe requisite pyrazole intermediate which is hydrolyzed to affordpyrazole acid intermediates of this invention such as 3c. Furthermoreamino pyrazole intermediates of this invention can be obtained byhydrolysis of the ester will give 3d. Diazotization of the amino moietyas in 3b in fluoroboric acid followed by heating at high temperatureshould then provide fluoropyrazole intermediates such as 3e.Appropriately substituted hydrazines can be condensed with (E)-ethyl2-((dimethylamino)methylene)-3-oxobutanoate to give, after hydrolysis,the methyl pyrazole derivatives 3f.

Alternative approaches to pyrazoles can also be obtained via theChan-Lam coupling as shown in Scheme 4. The requisite pyrazole (4b) andappropriately substituted boronic acids (4a) are commercially available.Alternatively these entities could be coupled via the Ullman couplingmethodology with CuI, K₂CO₃ in DMSO at 130° C. In these cases theboronic acid derivatives would be substituted with the arylbromides oriodides.

Imidazole acids of this invention such as 4af and 4ag can be prepared asoutlined in Scheme 4a. Ullman coupling between an appropriatelysubstituted imidazole 4aa and an appropriately substituted arylhalide4ab can provide the imidazole derivatives 4ad and 4ae in one step.Hydrolysis of the ester will generate the imidazole acids 4af and 4ag.Alternatively, an appropriately substituted imidazole 4aa can be coupledto an appropriately substituted arylboronic acid 4ac using a modifiedprocedure described by Sreedhar (Synthesis, 5:795 (2008)). Alternativeapproaches to the imidazole derivatives 4ad and 4ae can be achievedusing a modified procedure described by Gomez-Sanchez (J. HeterocyclicChem., 24:1757 (1987)). Condensation of the ethyl nitroacetate, triethylorthoformate, and an appropriately substituted aniline (4ah) can provideethyl 3-arylamino-2-nitroacrylate 4ai. The ethyl3-arylamino-2-nitrocrotonate derivatives 4aj can be prepared by reactingethyl 3-ethoxy-2-nitrocrotonate with an appropriately substitutedaniline 4ah. Reacting compounds 4ai and 4aj with triethyl orthoformateand platinum on carbon under a hydrogen atmosphere at elevatedtemperature can yield the imidazole derivatives 4ad and 4ae. Hydrolysisof the ester will generate the imidazole acids 4af and 4ag.

Bicyclic pyrazole intermediates of this invention can be constructed viathe methodology outline in Scheme 5. Reaction of the hydrazine (3a) withan appropriate aldehyde should afford the hydrazone 5a which onchlorination with NCS followed by condensation with an appropriatemalonate should lead to pyrazole such as 5b. Coupling of the requisiteacid with macrocyclic amines of this invention should lead tocarboxamide pyrazole 5c which can be converted to the compounds of thisinvention via methods outlined or known to those in the art.

Intermediates for preparation of compounds of this invention whereinring B is an imidazole ring, can be prepared from an appropriatelyN-protected allylglycine (6a) according to the general method outlinedin Scheme 6 (Contour-Galcera et al., Bioorg. Med. Chem. Lett.,11(5):741-745 (2001)). Condensation of 6a with a suitably substitutedbromoacetophenone (1b) in the presence of a suitable base such aspotassium bicarbonate, K₂CO₃ or Cs₂CO₃ in a suitable solvent such as DMFprovides a keto ester intermediate which can be cyclized to afford animidazole (6c) by heating in the presence of excess ammonium acetate ina solvent such as toluene or xylene. This latter transformation can beconveniently carried out on small scale at 160° C. in a microwavereactor or on larger scale by refluxing the mixture while removing watervia a Dean-Stark trap. The resulting imidazole intermediate (6c) is thenprotected by treatment with SEM-Cl in the presence of a base such assodium hydride or dicyclohexylmethylamine in a solvent such as THF orDCM. The aryl bromide (6d) is then converted to the correspondinganiline (6e) by heating in a sealed vessel with excess ammoniumhydroxide, in the presence of copper iodide, a base such as Cs₂CO₃ and acatalytic amount of proline in DMSO as solvent. Acylation of 6e with theappropriate alkenoic acid and a coupling agent such as T3P or BOPreagent, or alternately, by treatment with an alkenoic acid chloride inthe presence of a base such as TEA or DIEA provides diene 6f, whichundergoes ring closing metathesis by heating in dilute solution in thepresence of p-toluene sulfonic acid and Grubbs II catalyst in a suitablesolvent such as DCM or DCE to provide the corresponding macrocycle (6g)(Tetrahedron Letters, 44:1379 (2003)). Alternately, the RCM can be runin a microwave at elevated temperatures without pTsOH. Chlorination onthe imidazole ring with NCS, or initial reduction of the double bondfollowed by chlorination, and deprotection provides intermediates 6h and6i, respectively. Alternately, for compounds wherein R₁₀═CN, catalytichydrogenation of 6g followed by bromination with NBS at room temperatureand subsequent palladium-catalyzed cyanation and deprotection providesintermediate 6j. Intermediates 6h-j can be converted to compounds ofthis invention following the steps described in Scheme 15.

Representative imidazole containing amide macrocycle intermediatesuseful for the synthesis of compounds of this invention are described inScheme 7. The aniline 6e can be coupled with an appropriatelysubstituted carboxylic acid 7a using propane phosphonic acid anhydride(T3P) to give the amide 7b (n=0) and 7c (n=1). Using a modifiedprocedure described by Lovely (Tetrahedron Letters, 44:1379 (2003)), 7band 7c, following pretreatment with p-TsOH to form the imidazoliniumion, can be cyclized via ring-closing metathesis using a catalyst, suchas Grubbs (II), in a suitable solvent, such as DCM, DCE, or toluene atelevated temperature, to give the imidazole-containing macrocycles 7d(n=0) and 7e (n=1). The alkene can then be reduced with hydrogen overeither palladium on carbon or platinum oxide and subsequent deprotectionwith TFA in DCM provides amine 7f and 7g. Compounds of the formulae 7fand 7g can be converted to compounds in this invention according toScheme 15.

Representative regioisomeric imidazole containing amide macrocycleintermediates useful for the synthesis of compounds of this inventionare described in Scheme 7a. An appropriately N-protected allylglycine 6acan be converted to the bromoketone 7ab in two steps. Condensation of7ab with formamidine at elevated temperature generates the imidazole7ac. The imidazole 7ac can be protected with SEM-Cl and thendeprotonation with nBuLi and subsequent quenching with NBS provides thebromo imidazole 7ae. Suzuki-Miyaura coupling between bromo imidazole Taeand an appropriately substituted aryl or heteroaryl boronic acid orester 11e in the presence of a base such as K₃PO₄ using a precatalystsuch as Pd(dppf)Cl₂.CH₂Cl₂ complex provides, after separation of theenantiomers, aniline 7af. Aniline 7af can be converted to 7ag and 7ahaccording to Scheme 7. Compounds of the formulae 7ag and 7ah can beconverted to compounds in this invention according to Scheme 15.

Alternatively, imidazole containing macrocycles of this invention can bederived from intermediate 8e according to Scheme 8. Ullmann typecoupling reaction of compound 6d and allyl glycine, followed bymethylation of the acid would provide the extended aniline analog 8b.Ring closing metathesis of the diene 8b using Grubb II catalyst wouldprovide the macrocyclic olefin 8c. Then, the macrocyclic olefin 8c maybe converted to the key intermediate 8e via hydrogenation and selectivedeprotection of the amine protecting group from compound 8d. The amine8e may be converted to the corresponding cyclic carbamate or otheranalogs following the procedures described in Scheme 15. The otherdiastereomer at the methyl ester position can also be made in the sameway as described above.

The cyano or chloro imidazole analog of intermediate 8e may be obtainedby a slightly modified sequence of Scheme 9. The aniline nitrogen incompound 8b may be protected with a trifluoroacetyl group (TFA) in orderto suppress bromination/chlorination on the phenyl group duringconversion of compound 9b to 9c. Following the same sequence as outlinedin Scheme 8, the resulting protected aniline 9a may be converted tomacrocyclic compound 9b. Bromination or chlorination of 9b with NBS orNCS respectively provides intermediates 9c. For compounds wherein R¹⁰ isCN, bromide 9c is converted to cyanoimidazole 9d by palladium-catalyzedcyanation as described in Scheme 6 above. Selective removal of the amineprotecting group from compound 9d provides amine intermediates 9e. Forexample a Boc protecting group can be selectively removed either undermild acidic conditions or thermally by heating in trifluoroethanol in amicrowave at 150° C. Intermediate 9e can be converted to the finalcompounds described in this invention according to Scheme 15.

Alternatively, imidazole compounds of this invention can be derived fromtrifluoromethyl substituted macrocycle intermediates, 10c which can beprepared from aniline 6e following the sequence described in Scheme 10.A condensation reaction of the aniline 6e with trifluoroacetaldehydeethyl hemiacetal provides the aminal 10a. Treatment of 10a with allylGrignard reagent, provides aniline 10b, which is then converted to thetarget compound 10c via the sequence described in Scheme 6.

Representative compounds of this invention where ring B is asix-membered heterocycle (example—pyridine) can be derived fromintermediates 11l, the synthesis of which is described in Scheme 11.Condensation of aldehyde 11a (X═N) prepared according to a modifiedprocedure described by Negi (Synthesis, 991 (1996)), with(S)-2-methylpropane-2-sulfinamide in the presence of anhydrous coppersulfate in a solvent such as DCM gives the sulfinimine 11b (Ellman, J.,J. Org. Chem., 64:1278 (1999)). Using a modified procedure described byKuduk (Tetrahedron Letters, 45:6641 (2004)), suitably substitutedGrignard reagents, for example allylmagnesium bromide, can be added tosulfinimine 11b to give a sulfinamide 11c, as a mixture of diastereomerswhich can be separated at various stages of the sequence. Thediastereoselectivity for the addition of allylmagnesium bromide tosulfinimine 11b can be improved by employing indium(III) chlorideaccording to a modified procedure of Xu (Xu, M-H, Organic Letters,10(6):1259 (2008)). Suzuki-Miyaura coupling between 4-chloropyridine 1cand an appropriately substituted aryl or heteroaryl boronic acid orester 11e in the presence of a base such as potassium phosphate, in asolvent mixture, such as DMSO and H₂O, or DMF, using a precatalyst suchas Pd(dppf)Cl₂.CH₂Cl₂ complex provides 11g. Alternatively, theSuzuki-Miyaura coupling between boronic acid 11d and an appropriatelysubstituted aryl or heteroaryl halide 11f can be used to prepared 11g.Protecting group interconversion can be accomplished in two steps togive 11h. Alternatively, the protecting group interconversion can takeplace initially on 11c followed by the Suzuki-Miyaura coupling. Theaniline 11h can then be coupled with an appropriately substitutedcarboxylic acid 11i using T3P and a base, such as pyridine, to give theamide 11j. Using a modified procedure described by Lovely (TetrahedronLetters, 44:1379 (2003)), 11j, following pretreatment withp-toluenesulfonic acid to form the pyridinium ion, can be cyclized viaring-closing metathesis using a catalyst, such as Grubbs (II), in asuitable solvent, such as DCM, DCE, or toluene at elevated temperature,to give the pyridine-containing macrocycle 11k. The alkene can bereduced with hydrogen over either palladium on carbon or platinum oxide,and subsequent deprotection with TFA in DCM or 4M HCl in dioxaneprovides amine 11l. Compounds of the formulae 11l can be converted tocompounds in this invention according to Scheme 15.

Additional pyridine containing macrocycles useful for the synthesis ofcompounds of this invention can also be prepared according to Scheme 11.In cases where the pyridine core is a 4-pyridine (Z═N) rather than the2-pyridine (X═N), conversion of 11h to 11j can be easily accomplished byusing an acid chloride of 11i. Intermediates of formulae 11g whereR⁸═NO₂ may be modified further to give intermediates where R⁸═NHCO₂—C₁₋₄ alkyl either before coupling with acid 11i or after couplingwith acid. Reduction of the nitro group to an amino group may beaccomplished with a reducing agent (e.g., Zn—NH₄Cl) in an inert solvent(e.g., MeOH) to give an intermediate of formula 11g where R⁸═NH₂. Theseanilino derivatives may be coupled with chloroalkanoates of the formulaClCO₂—C₁₋₄ alkyl in the presence of a base (e.g., DIEA) in an inertsolvent (e.g., DCM) to give intermediates where R⁸═NH CO₂—C₁₋₄ alkyl.

The amino ester analog 13e was obtained from key intermediate 12jfollowing the sequence described in Scheme 13. Step-wise imine formationof 12j with ethyl 2,3-dioxopropanoate followed by addition ofallyltributyltin under tin (IV) chloride conditions afforded RCMprecursor 13a. Following the same sequence in Scheme 12, 13a can beconverted into critical intermediate 13e over several steps. Othermacrocyclic intermediates such as 13e wherein the ester is replaced witha variety of substituents can also be similarly constructed andfollowing the sequence of reactions outlined above can be converted tocompounds of this invention according to Scheme 15.

Methods for synthesis of a large variety of substituted pyridinecompounds useful as starting materials for the preparation of compoundsof the present invention are well known in the art and have beenextensively reviewed. (For examples of methods useful for thepreparation of pyridine starting materials see: Kroehnke, F., Synthesis,1 (1976); Abramovitch, R. A., ed., “Pyridine and Its Derivatives”, TheChemistry of Heterocyclic Compounds, 14(Suppl. 1-4), John Wiley & Sons,New York (1974); Boulton, A. J. et al., eds., Comprehensive HeterocyclicChemistry, 2:165-524, Pergamon Press, New York (1984); McKillop, A.,ed., Comprehensive Heterocyclic Chemistry, 5:1-300, Pergamon Press, NewYork (1996)).

In cases where suitably substituted boronic acids are not commerciallyavailable, a modification to this approach may be adopted wherein anaryl halide is subjected to a palladium mediated coupling with a diboronspecies such as bis(pinacolato)diboron or bis(neopentylglycolato)diboron to provide the corresponding4,4,5,5-tetramethyl-[1,3,2]dioxaborolane or the5,5-dimethyl-[1,3,2]dioxaborolane intermediates using the method ofIshiyama, T. et al. (J. Org. Chem., 60(23):7508-7510 (1995)).Alternately, this same intermediate can be prepared by reaction of theintermediate halide with the corresponding dialkoxyhydroborane asdescribed by Murata et al. (J. Org. Chem., 62(19):6458-6459 (1997)). Theboron pinacolate intermediates can be used in place of boronic acids forcoupling to the aryl/heteroaryl halides or triflates or the boronpinacolate intermediate can be converted to the boronic acids.Alternately, the corresponding boronic acids can be prepared bymetal-halogen exchange of the aryl/heteroaryl halide, quenching with atrialkoxyborate reagent, and aqueous workup to provide the boronic acids(Miyaura, N. et al., Chem. Rev., 95:2457 (1995)).

It is also realized that the scope of intermediate synthesis can befurther extended outside the use of Suzuki-Miyaura coupling methodologysince the precursor aryl halides or triflates described above are alsoprecursors for Stille, Negishi, Hiyama, and Kumada-type cross couplingmethodologies (Tsuji, J., Transition Metal Reagents and Catalysts:Innovations in Organic Synthesis, John Wiley & Sons (2000); Tsuji, J.,Palladium Reagents and Catalysts: Innovations in Organic Synthesis, JohnWiley & Sons (1996)).

Additional pyridazine and pyridazinone containing macrocycles can beprepared according to Scheme 14. Condensation of the potassium salt of14a with a suitably substituted α-ketoester 14b, which is eithercommercially available or prepared using a modified procedure describedby Domagala (Tetrahedron Lett., 21:4997-5000), in a solvent such as THFgenerates the α,β-unsaturated ketone derivative which can then becondensed with a suitably substituted hydrazine derivative to givepyridazinone 14c. The nitro group can then be reduced to the aniline 14fwith zinc and NH₄Cl in methanol. The pyridazinone 14c can be convertedto chloro-pyridazine 14d by deprotection of the amine protecting group,followed by treatment with POCl₃, then reprotection. The nitro group canbe reduced to the aniline 14e with iron and AcOH. The anilines 14e and14f can then be coupled with an appropriately substituted carboxylicacid 7a using T3P to give the amide 14g (R₁₀═Cl) and 14h (R₁₀═OH),respectively. 14g and 14h can then be cyclized via ring-closingmetathesis using a catalyst, such as Grubbs (II), in a suitable solvent,such as DCM, DCE, or toluene at elevated temperature, to give themacrocycle 14i (R₁₀═Cl) and 14j (R₁₀═OH), respectively. The resultingalkenes can then be reduced with hydrogen over either palladium oncarbon or platinum oxide to give 14k and 14l. 14k can be reduced withammonium acetate and palladium on carbon to reduce the chlorine to give14m. Subsequent deprotection of 14m and 14l provides amines 14n (R₁₀═H)and 14o (R₁₀═OH). Compounds of the formulae 14n and 14o can be convertedto compounds in this invention according to Scheme 15.

Representative regioisomeric pyridazine containing amide macrocycleintermediates useful for the synthesis of compounds of this inventionare described in Scheme 14a. Using a modification of the Miniscireaction described by Cowden (Org. Leu., 5:4497-4499 (2003)), anappropriately protected glycine 14aa and 3,6-dichloropyridazine can becoupled at elevated temperature in the presence of silver nitrate,ammonium persulfate, and an acid, such as ammonium formate, in asolvent, such as water or a water/dimethylformamide mixture, to givecompounds of the formulae 14ab. Compound 14ab can be furtherfunctionalized by deprotonation with nBuLi and subsequent alkylationwith an appropriately substituted alkyl halide, for instance allylbromide, to give compound 14ac. Suzuki-Miyaura coupling betweenchloropyridazine 14ac and an appropriately substituted aryl orheteroaryl boronic acid or ester 11e in the presence of a base such assodium carbonate using a precatalyst such as (Ph₃P)₄Pd provides, afterseparation of the enantiomers, aniline 14ad. Aniline 14ad can beconverted to 14ae and 14af according to Scheme 7. Hydrogenolysis of thechloro under transfer hydrogenation conditions and Boc-deprotection willgive compounds 14ag and 14ah. Compounds of the formulae 14ag and 14ahcan be converted to compounds in this invention according to Scheme 15.

Representative compounds of this invention can then be made as shown inScheme 15 using intermediates made in Schemes 2 to 13. The varioussubstituted acids represented by formula 15b can be coupled with both 6-and 5-membered macrocycle amines represented by 15a using eithercoupling reagents or by converting them to acid chloride (like Vilsmeierreagent) and then treating the mixture with a base to afford the desiredmacrocycles of this invention.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutingwith either gradients of hexanes and EtOAc or DCM and MeOH unlessotherwise indicated. Reverse phase preparative HPLC was carried outusing C18 columns eluting with gradients of Solvent A (90% H₂O, 10%MeOH, 0.1% TFA) and Solvent B (10% H₂O, 90% MeOH, 0.1% TFA, UV 220 nm)or with gradients of Solvent A (90% H₂O, 10% ACN, 0.1% TFA) and SolventB (10% H₂O, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients of Solvent A(98% H₂O, 2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2% H₂O, 0.05% TFA,UV 220 nm) (or) Sunfire Prep C18 OBD 5u 30×100 mm, 25 min gradient from0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA 90:10:0.1.

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC.

Method A: A majority of analytical HPLC runs were: SunFire (3.0×150 mm)(15 min gradient—95:5 H₂O/ACN-to 95:5 ACN/H₂O—0.05% TFA).

Method B: ZORBAX® (4.6×75 mm) (8 min gradient—10:90 MeOH/H₂O to 90:10MeOH/H₂O, 0.2% H₃PO₄)

Method C: PHENOMENEX® Luna 5μ 4.6×50 mm (4 min gradient—10:90 ACN/H₂O to90:10 ACN/H₂O—0.1% TFA)

Method D: SunFire column (3.5 μm C18, 3.0×150 mm) Gradient elution (1.0mL/min) from 10-100% Solvent B for 10 min and then 100% Solvent B for 5min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) andSolvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

Method E: SunFire column (3.5 μm C18, 3.0×150 mm) Gradient elution (1.0mL/min) from 10-100% Solvent B for 12 min and then 100% Solvent B for 3min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) andSolvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

A majority of mass spectra runs were: LCMS(ESI) m/z: [M+H]⁺ PHENOMENEX®Luna C18 (2×30 mm) (2 min gradient 90% H₂O/10% MeOH/0.1% TFA to 90%MeOH/10% H₂O/0.1% TFA) (or) BEH C18 2.1×50 mm—2 min gradient from 0-100%B. (A: 90/10/0.1 H₂O/ACN/TFA; B: 90/10/0.1 ACN/H₂O/TFA).

Intermediate 11-(3-Chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 1.1-(3-Chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid:3-chloro-2-fluoro aniline was dissolved in TFA (4 mL) and H₂O (2 mL) wasadded to the above solution. The mixture was then cooled to 0° C. and tothis was added a predissolved aqueous solution (2 mL) of NaNO₂ dropwiseto ensure the temperature did not rise above 5° C. The reaction mixturewas stirred at this temperature for 0.5 h followed by the addition ofsolid NaN₃ portionwise. The reaction mixture was stirred cold and thenallowed to warm up to rt overnight. The reaction mixture was quenchedwith H₂O (100 mL) and extracted the azide with EtOAc (2×50 mL), driedand evaporated to a solid mass (1.1 g). The product obtained wasdissolved in DMSO (5 mL) in a microwave flask and to this was addedL-proline (0.02 g), Cu(OAc)₂ (0.1 g), K₂CO₃ (1.5 g) and sodium ascorbate(0.1 g) and excess t-butyl propiolate (3 mL). The flask was sealed andheated at 75° C. overnight. Aliquot LCMS showed the reaction to becomplete. The reaction mixture was quenched with H₂O (100 mL) andextracted the organic layer with EtOAc (2×100 mL), washed with brine (50mL) and dried (MgSO₄). The crude product was then purified using silicagel chromatography. The desired ester was isolated and concentrated,evaporated to a brown solid (0.98 g). The ester (0.2 g) was dissolved inDCM (2 mL) and to this was added TFA (1 mL) and stirred at rt overnight.Aliquot LCMS showed the reaction to be complete. The reaction mixturewas then quenched with H₂O (50 mL) and the organic layer was extractedwith EtOAc (2×100 mL), dried and evaporated to a brown solid mass.MS(ESI) m/z: 342.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (s, 1H),7.60-7.55 (dt, 1H), 7.42-7.37 (dt, 1H), 7.28-7.23 (dt, 1H) ppm.

Intermediate 2 1-(3-Chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid

Intermediate 2A. Ethyl5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate: To amixture of (3-chloro-2-fluorophenyl)hydrazine hydrochloride (0.67 g,3.40 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.633 g, 3.72 mmol) andsodium acetate (0.586 g, 7.12 mmol) at rt was added AcOH and H₂O to forma slurry. The reaction mixture was continued to stir at rt for 0.25 hand then heated at 100° C. for overnight. After overnight stirring, thereaction mixture was quenched with H₂O (200 mL) and a yellowish brownsolid separated. The solids were filtered and washed thoroughly withH₂O. Re-dissolved the residue in DCM, dried and evaporated to a brownsolid as the desired product (0.76 g, 78%). MS(ESI) m/z: 284.2 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.51-7.29 (m, 2H), 7.27-7.03 (m,1H), 5.30-5.06 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 1.38-1.04 (m, 3H) ppm.

Intermediate 2. 1-(3-Chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylicacid: A mixture of Intermediate 2A (0.317 g, 1.117 mmol), isoamylnitrite(1.304 g, 11.14 mmol) in THF (20 mL) was heated at 100° C. After 2 h,the reaction mixture was concentrated in vacuo to yield the crudeproduct. To the crude product was added NaOH (0.610 g, 10 Eq), MeOH andH₂O. The reaction mixture was stirred at rt for 2 h. The reactionmixture was then quenched with H₂O (100 mL) and extracted the unreactedstarting material with EtOAc (2×100 mL). The aqueous layer was thenacidified with HCl (1 N) and then extracted the organics with EtOAc(2×100 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated to give Intermediate 2 as a brown solid mass.MS(ESI) m/z: 240.9 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=2.5 Hz,1H), 8.12 (s, 1H), 7.77 (ddd, J=8.3, 6.9, 1.8 Hz, 1H), 7.41-7.28 (m,1H), 7.23-7.10 (m, 1H) ppm.

Intermediate 3 5-Amino-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylic acid

Intermediate 3A.Ethyl-5-amino-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylate: (Ref: J.Heterocyclic Chem., 267 (1987)) To a mixture of(3-chlorophenyl)hydrazine hydrochloride (2.328 g, 13 mmol), (E)-ethyl2-cyano-3-ethoxyacrylate (2.199 g, 13.00 mmol) and K₂CO₃ (1.797 g, 13.00mmol) was added EtOH (20 mL). The suspension was then warmed to refluxand stirred at refluxing temperatures for overnight. After 20 h, thereaction mixture was poured into ice-H₂O. The suspension was thenfiltered and the solid collected by filtration was dried in vacuo (50°C.) for overnight to yield a brown solid (2.93 g). MS(ESI) m/z: 266.1(M+H)⁺.

Intermediate 3. 5-Amino-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylicacid: (Reference: J. Heterocyclic Chem., 773 (2003)) A solution ofIntermediate 3A (0.652 g, 2.454 mmol) and NaOH (0.613 g, 15.34 mmol) inEtOH (1.534 mL) and H₂O (13.80 mL) was refluxed until the reactionmixture became homogeneous. After 24 h, the reaction mixture was cooledto rt and filtered. The filtrate was acidified with concentrated HCl togive a suspension which was subjected to filtration. The solid collectedby filtration was washed with H₂O and dried in vacuo (50° C.) for 4 h togive a yellow solid (0.51 g) as the desired product. MS(ESI) m/z: 238.1(M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 7.77 (s, 1H), 7.64-7.61 (m, 1H),7.58-7.51 (m, 2H), 7.50-7.46 (m, 1H) ppm.

Intermediate 45-Amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid

Intermediate 4A. Ethyl5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate: A brownsuspension of (3-chloro-2-fluorophenyl)hydrazine hydrochloride (0.500 g,2.54 mmol) and (E)-ethyl 2-cyano-3-ethoxyacrylate (0.472 g, 2.79 mmol)in EtOH (2.54 mL) and triethylamine (0.707 mL, 5.08 mmol) was warmed to85° C. After 4.5 h, the reaction was stopped and cooled to rt. Thereaction was concentrated to give a brown solid. Purification by normalphase chromatography gave Intermediate 4A (0.185 g, 26%) as an off-whitesolid. MS(ESI) m/z: 284.0 (M+H)⁺.

Intermediate 4.5-Amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid: Aclear, dull yellow solution of Intermediate 4A (0.184 g, 0.649 mmol) inMeOH (3.24 mL) and 1.0 N NaOH (1.946 mL, 1.946 mmol) was stirred at rt.After 1 h, the reaction was warmed to 50° C. After 8 h, the reaction wasstopped and cooled to rt. The clear, yellow orange solution wasconcentrated to give a white solid. The white solid was partitionedbetween EtOAc, water, and 1.0 N NaOH and the layers were separated. Theaqueous layer was extracted with EtOAc. The aqueous layer was acidifiedwith 1.0 N HCl and then extracted with EtOAc (2×). The combined organiclayers, following acidification, were washed with brine, dried oversodium sulfate, filtered and concentrated to give Intermediate 4 (0.153g, 92%) as an off-white solid. MS(ESI) m/z: 256.0 (M+H)⁺ and 258.0(M+2+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.02 (br. s., 1H), 7.74 (ddd,J=8.1, 6.7, 1.7 Hz, 1H), 7.69 (s, 1H), 7.50 (td, J=7.4, 1.7 Hz, 1H),7.37 (td, J=8.0, 1.2 Hz, 1H), 6.43 (s, 2H).

Intermediate 51-(3-Chloro-2,6-difluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 5A: tert-Butyl (3-chloro-2,6-difluorophenyl)carbamate:3-chloro-2,6-difluorobenzoic acid (4.85 g, 25.2 mmol) was dissolved inTHF (50 mL) and cooled to 0° C. To this solution was then addedethylchloroformate (3.01 g, 27.7 mmol) followed by TEA (3.86 mL, 27.7mmol) and stirred at the same temperature for 1 h. To the slurry thatdeveloped was then added NaN₃ in H₂O (5 mL) dropwise and stirred thereaction mixture at 0° C. for 1.25 h. Solids separated out from thereaction mixture and allowed the solids to decant followed by separationof the decantant. The residue was dissolved in H₂O (50 mL) and extractedwith DCM (2×). The above organic layer was then combined with thedecantant, dried (MgSO₄) and concentrated to yield a residue. Theresidue was re-dissolved in toluene (50 mL) and heated at 110° C. To theabove solution was added t-BuOH (1.5 g) and refluxed for overnight. Thereaction mixture was concentrated and purified by silica gelchromatography to yield the desired product (2.86 g, 43%). MS(ESI) m/z:286.0 (M+Na)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.28 (s, 1H), 7.03-6.72 (m,1H), 6.10-5.83 (m, 1H), 1.57-1.37 (m, 9H) ppm.

Intermediate 5B. tert-Butyl1-(3-chloro-2,6-difluorophenyl)-1H-1,2,3-triazole-4-carboxylate: To asolution of Intermediate 5A in DCM (5 mL) was added TFA (1 mL) andstirred at rt for 1 h. The reaction mixture was then concentrated toyield a brown oil which was redissolved in TFA (5 mL) and cooled to 0°C. To this cooled solution was then added NaNO₂ (0.209 g, 3.03 mmol) inH₂O (1 mL) dropwise. The reaction mixture was allowed to stir at 0° C.for 0.5 h followed by the addition of NaN₃ (0.394 g, 6.07 mmol) in H₂O(1 mL). The reaction mixture was continued to stir for 2 h at the sametemperature and then quenched with H₂O (100 mL) and extracted theaqueous layer with EtOAc (2×). The combined organic layers were driedand evaporated to a brown oil. The azide from the above reaction wasthen dissolved in DMSO (5 mL) and to this solution was addedt-butylpropiolate (1.5 mL, 1.517 mmol), Cu(OAc)₂ (0.055 g, 0.303 mmol)and K₂CO₃ (0.839 g, 6.07 mmol). The reaction was stirred at rt forovernight. The reaction mixture was then quenched with H₂O and solidmass separated. The reaction mixture was extracted with EtOAc (2×). Theorganic layer was dried and evaporated to a dark brownish-black oil. Thecrude product was then purified using silica gel chromatography. Thedesired product was isolated as reddish oil (0.3 g, 62%). MS(ESI) m/z:316.0 (M+H)⁺.

Intermediate 5.1-(3-Chloro-2,6-difluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid: Toa solution of Intermediate 5B (0.3 g, 0.950 mmol) in DCM (5 mL) wasadded TFA (1 mL) and the reaction mixture was stirred at rt for 1 h. Thereaction mixture was then concentrated to yield the crude product whichwas purified using reverse phase HPLC. MS(ESI) m/z: 260.0 (M+H)⁺. ¹H NMR(400 MHz, MeOD) δ 8.94 (s, 1H), 7.85 (ddd, J=9.3, 8.1, 5.3 Hz, 1H), 7.40(td, J=9.2, 2.0 Hz, 1H) ppm.

Intermediate 6 1-(3-Chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 6A. Ethyl1-(3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylate: Sodium nitrite(1.947 g, 28.2 mmol) dissolved in H₂O (5 mL) was added to a cold (<5°C.) TFA (20 mL) solution of 3-chloro aniline (3.6 g, 28.2 mmol). After0.5 h, sodium azide (1.835 g, 28.2 mmol) dissolved in H₂O (1 mL) wasadded dropwise to the above reaction mixture. The reaction mixture wasthen stirred cold for 2 h and then quenched with H₂O (100 mL) andextracted the organics with EtOAc (2×100 mL). The organic layers werethen dried over MgSO₄ and concentrated to a brown oil (3.5 g).Approximately 1 g of the azide from the above crude product was taken ina microwave flask. To this was added ethyl propiolate (1.5 mL), DMSO (4mL), sodium carbonate (0.1 g) and L-proline (0.1 g) and the reactionmixture was heated at 75° C. overnight. The reaction was then quenchedwith H₂O to precipitated out the solids. Filtered the solids and washedwith excess H₂O followed by drying under vacuum to afford 1.3 g of thedesired triazole ester. MS(ESI) m/z: 252.1 (M+H)⁺.

Intermediate 6. 1-(3-Chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid:To a solution for Intermediate 6A (0.3 g, 1.192 mmol) in a mixture ofTHF and H₂O (1:1) was added LiOH and stirred at rt for 1 h. After 1 h,the reaction mixture was quenched with H₂O (50 mL) and extracted theunreacted starting material with EtOAc. The aqueous layer was thenacidified and extracted the acid with EtOAc (2×100 mL). The organiclayers were then dried over MgSO₄ and evaporated to a brown oil whichsolidified at rt. MS(ESI) m/z: 224.0 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ9.13 (s, 1H), 8.03 (s, 1H), 7.89 (dd, J=2.2 & 8.4 Hz, 2H), 7.61-7.56 (m,2H) ppm.

Intermediate 7 1-(3-Chlorophenyl)-1H-pyrazole-4 carboxylic acid

Intermediate 7. 1-(3-Chlorophenyl)-1H-pyrazole-4 carboxylic acid:1-(1-(3-Chlorophenyl)-1H-pyrazol-4-yl)ethanone was dissolved in asolution of MeOH and DMSO (5:1). To this solution was then added asolution of NaOMe (2 N, 10 mL) followed by bleach (20 mL) and stirred atrt for overnight. After overnight stirring, the reaction mixture wasquenched with H₂O (200 mL) and acidified with concentrated HCl.Extracted the organics with EtOAc (2×100 mL) and concentrated to yield abrown solid as the desired product. MS(ESI) m/z: 223.1 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 7.36-7.38 (m, 1H), 7.47-7.51 (m, 1H), 7.74-7.77 (m,1H), 7.89-7.90 (m, 1H), 8.04 (s, 1H), 8.65 (s, 1H) ppm.

Intermediate 8 5-Amino-1-(3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylicacid

Intermediate 8.5-Amino-1-(3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid: Theazide was made as previously described (Intermediate 6) starting with3-chloroaniline. The azide was then treated with tert-butyl2-cyanoacetate under refluxing conditions for overnight. After overnightstirring, the reaction mixture was quenched with H₂O (100 mL) andextracted with EtOAc (2×100 mL). The organic layers were then dried(MgSO₄) and evaporated to a brown solid. The brown solid was thenre-dissolved in DCM (2 mL) and to this solution was added TFA (2 mL) andstirred at rt for overnight. The reaction mixture was then concentratedand quenched with H₂O to precipitate out a brown solid. The solids werefiltered, washed with excess MeOH and dried to afford brownish whitesolid. MS(ESI) m/z: 238.9 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ 7.75 (bs,1H), 7.37-7.34 (dd, J=1.7 & 8.3 Hz, 1H), 7.25-7.21 (t, 1H), 6.91-6.89(bd, 1H) ppm.

Intermediate 91-(3-Chlorophenyl)-3-(2-hydroxyethyl)-1H-pyrazole-4-carboxylic acid

Intermediate 9A: 3-((tert-Butyldiphenylsilyl)oxy)propanal: To a solutionof tert-butyldiphehenylsilylchloride (2.20 g, 8.0 mmol) in DCM/DMF(95:1) was added 1,3 propanediol (2.010 g, 26.4 mmol) followed by TEA(1.053 g, 10.43 mmol) and catalytic DMAP (0.049 g, 0.4 mmol) and thereaction mixture was stirred at rt overnight. The reaction mixture wasthen quenched with H₂O (200 mL) and extracted the organics with EtOAc(3×). The crude product in a solution of DCM (5 mL) was added slowly toa cooled solution (−78° C.) of oxalyl chloride (5.75 mL, 11.59 mmol) inDCM (20 mL). The reaction mixture was continued to stir at −78° C. for20 min and then treated with TEA (5.34 mL, 38.3 mmol) and then raised tort slowly. The reaction mixture was then diluted with ether, washed with10% aqueous citric acid followed by brine. The organic layers were thendried and concentrated to give the desired product. ¹H NMR (400 MHz,CDCl₃) δ 7.90-7.56 (m, 4H), 7.49-7.28 (m, 6H), 3.96-3.61 (m, 2H), 2.27(br. s., 1H), 1.88-1.72 (m, 2H), 1.16-0.96 (m, 9H) ppm.

Intermediate 9B:(E)-1-(3-((tert-Butyldiphenylsilyl)oxy)propylidene)-2-(3-chlorophenyl)hydrazine:A solution of (3-chlorophenyl)hydrazine hydrochloride and TEA (3 mL,21.5 mmol) and 3-(tert-butyldiphenylsilyloxy)propanal (21.5 mmol) intoluene was stirred at rt overnight. The reaction mixture was thenquenched with H₂O (100 mL) and extracted with EtOAc (2×). The organiclayers were dried (MgSO₄) and evaporated to a reddish oil. The crudeproduct was then purified using silica gel chromatography. The desiredproduct was isolated as a red oil. MS(ESI) m/z: 437.1 (M-Boc)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.84-7.59 (m, 4H), 7.50-7.29 (m, 6H), 7.18-6.90 (m,1H), 6.77 (dt, J=8.1, 2.0 Hz, 1H), 3.98-3.68 (m, 2H), 2.63-2.38 (m, 2H),1.12-0.90 (m, 9H) ppm.

Intermediate 9B. Ethyl5-amino-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylate:To a solution of Intermediate 9A (1.34 g, 3.1 mmol) in DMF (5 mL) wasadded NCS (0.455, 3.41 mmol) and stirred at rt. After 4 h, the reactionmixture was quenched with H₂O (100 mL) and extracted with EtOAc (2×).The organic layers were dried (MgSO₄) and evaporated to a reddish oil.Separately ethylcyanoacetate (0.351 g, 3.10 mmol) was dissolved in EtOH(5 mL) and to this solution was added NaOEt (21%) (1.16 mL, 3.10 mmol)and the reaction was stirred at rt for 0.5 h followed by theintroduction of the iminochloride crude mixture. The above mixture wasthen stirred at rt. After 2 h, the reaction was quenched with H₂O andextracted with EtOAc (2×). The organic layers were dried (MgSO₄) andevaporated to yield orange-red oil. The crude product was then purifiedusing silica gel chromatography. Two peaks were isolated—one is thedesired product and the other is the chlorinated pyrazoline compound andthe two products were taken to the next step as a crude mixture. MS(ESI)m/z: 548.1 (M+H)⁺.

Intermediate 9C. Ethyl3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylate:Isoamylnitride (1 mL) was added to a THF solution of Intermediate 9B(crude mixture) and stirred at 70° C. overnight. The reaction mixturewas concentrated and taken to the next step as a crude mixture. MS(ESI)m/z: 555.3 (M+Na)⁺.

Intermediate 9.1-(3-Chlorophenyl)-3-(2-hydroxyethyl)-1H-pyrazole-4-carboxylic acid: Toa stirring THF solution of Intermediate 9C (0.5 g, 0.938 mmol) was added1 M nBu₄NF (2.81 mL, 2.81 mmol) in THF and the reaction mixture wasstirred vigorously at rt overnight. The reaction mixture was thenquenched with H₂O (100 mL) and extracted with EtOAc (2×). The combinedorganic layers were dried (MgSO₄) and concentrated to an oil. The crudeproduct was then purified using reverse phase HPLC to yield the desiredproduct (0.045 g, 16%) as oil. MS(ESI) m/z: 295.1 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 7.83 (s, 1H), 7.59-7.42 (m, 2H), 7.31-7.18(m, 1H), 5.42 (br. s., 1H), 4.80-4.65 (m, 1H), 4.42-4.26 (m, 2H),4.14-3.93 (m, 2H), 3.51-3.38 (m, 1H), 3.26 (t, J=5.8 Hz, 3H) ppm.

Intermediate 10 1-(3-Chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid

Intermediate 10. 1-(3-Chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid:(Reference: J. Med. Chem., 30:400-405 (1987)) A mixture of3-chloroaniline (2.55 g, 20 mmol) and 2-methylenesuccinic acid (2.60 g,20.00 mmol) was heated at 120° C. (open flash). After 20 min, thereaction was cooled to rt. Next, water was added and the reactionmixture was warmed to 110° C. (sealed tube) to give a yellow suspension.After cooling to rt, the yellow oil slowly solidifies to which was addedMeOH (20 mL) to give a yellow solution. After 1 h, the mixture wasfiltered and the solid rinsed with a small amount of MeOH and air-driedto yield an off-white solid as Intermediate 10 (2.5 g, 52%). MS(ESI)m/z: 240.0 (M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 7.80 (t, J=2.1 Hz, 1H),7.49-7.46 (m, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.18 (ddd, J=8.0, 2.1, 1.0Hz, 1H), 4.16-4.07 (m, 2H), 3.46-3.38 (m, 1H), 2.88 (dd, J=8.3, 1.1 Hz,2H).

Intermediate 11 1-(3-Chlorophenyl)pyrrolidine-3-carboxylic acid

Intermediate 11A. Methyl1-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylate (Ref: Tetrahedron,62:4011-4017 (2006)). To a cold solution of MeOH (8.35 mL) (0° C.) wasadded thionyl chloride (0.335 mL, 4.59 mmol) dropwise. After 30 min,Intermediate 10 (1 g, 4.17 mmol) was added, and the reaction mixture waswarmed to rt. The reaction mixture was then concentrated and the residuedissolved in EtOAc, washed with saturated NaHCO₃, H₂O and brine. Theorganic layers were dried over Na₂SO₄, filtered and concentrated toyield the desired product (1.04 g, 98%) as yellow oil. MS(ESI) m/z:254.0 (M+H)⁺.

Intermediate 11B. Methyl 1-(3-chlorophenyl)pyrrolidine-3-carboxylate: Toa solution of Intermediate 11A (0.27 g, 1.064 mmol) in THF (3 mL) wasadded BH₃-THF complex (1.596 mL, 1.596 mmol) (1 M in THF). The reactionmixture was stirred at rt. After 17 h, the reaction mixture was quenchedby adding 1 mL MeOH, then H₂O. The above mixture was then extracted withEtOAc and the organic layers were washed with H₂O, brine, dried overNa₂SO₄, filtered and concentrated. The crude product was then purifiedusing silica gel chromatography to afford a colorless oil as the desiredproduct (0.175 g, 68.6%). MS(ESI) m/z: 240.1 (M+H)⁺.

Intermediate 11. 1-(3-Chlorophenyl)pyrrolidine-3-carboxylic acid: To asolution of methyl 1-(3-chlorophenyl)pyrrolidine-3-carboxylate (0.175 g,0.730 mmol) in MeOH (5 mL) was added 1N NaOH (1.460 mL, 1.460 mmol). Thereaction mixture was stirred at rt for 2 h. After 2 h, the reactionmixture was then concentrated to remove MeOH. The residue was thenneutralized with 1 N HCl (2 mL) and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. A white solid was obtained as the desired product (0.15 g,91%). MS(ESI) m/z: 226.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.34 (br.s., 1H), 7.16 (t, J=8.1 Hz, 1H), 6.72-6.68 (m, 1H), 6.57 (t, J=2.2 Hz,1H), 6.49-6.43 (m, 1H), 3.64-3.52 (m, 2H), 3.48-3.25 (m, 3H), 2.43-2.29(m, 2H) ppm.

Intermediate 12 1-(3-Chlorophenyl)-1H-imidazole-4-carboxylic acid, HCl

Intermediate 12A. Ethyl 1-(3-chlorophenyl)-1H-imidazole-4-carboxylate, 1

TFA: A mixture of 1-chloro-3-iodobenzene (0.170 g, 0.714 mmol), ethyl1H-imidazole-4-carboxylate (0.1 g, 0.714 mmol), copper(I) iodide (0.027g, 0.143 mmol), and K₂CO₃ (0.296 g, 2.141 mmol) in DMSO (1.427 mL) wasvacuumed and back-filled with argon for three times, then capped andheated at 110° C. After 16 h, the reaction was cooled to rt and was thendiluted with EtOAc, washed with H₂O followed by brine. The organic layerwas then dried over Na₂SO₄, filtered, and concentrated. The crudeproduct was purified using silica gel chromatography to afford a whitesolid as the desired product (0.118 g, 66%). MS(ESI) m/z: 251.0 (M+H)⁺.

Intermediate 12. 1-(3-Chlorophenyl)-1H-imidazole-4-carboxylic acid: To asolution of Intermediate 12A (0.118 g, 0.471 mmol) in MeOH (4.71 mL) wasadded 1 N NaOH (0.941 mL, 0.941 mmol) and the reaction mixture wasstirred at rt. After 2 h, the reaction mixture was concentrated and theresidue was dissolved in MeOH/H₂O. To the above solution was then added1 N HCl (1.5 mL) to afford a white suspension which was filtered toisolate the solid. The solid was rinsed with H₂O and then dried in avacuum oven (50° C.) for 4 h to yield a white solid as Intermediate 12(0.09 g, 74%). MS(ESI) m/z: 223.0 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ8.44-8.23 (m, 2H), 7.77 (t, J=1.9 Hz, 1H), 7.63-7.45 (m, 3H) ppm.

Intermediate 13 1-(3-Chloro-2-fluorophenyl)-1H-imidazole-4-carboxylicacid, 1 TFA

Intermediate 13A. Ethyl1-(3-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate, 1 TFA: A mixtureof 1-chloro-2-fluoro-3-iodobenzene (0.549 g, 2.141 mmol), ethyl1H-imidazole-4-carboxylate (0.3 g, 2.141 mmol), copper(I) iodide (0.082g, 0.428 mmol), L-proline (0.099 g, 0.856 mmol), and K₂CO₃ (0.888 g,6.42 mmol) in DMSO (4.28 mL) was vacuumed and back-filled with argon forthree times, then capped and heated at 110° C. After 20 h, the reactionmixture was cooled to rt and diluted with EtOAc. The organic layer waswashed with H₂O, brine, dried over Na₂SO₄, filtered, and concentrated.The crude product was then purified using reverse phase HPLCchromatography to yield the desired product (0.01 g, 1.2%) as acolorless oil. MS(ESI) m/z: 269.0 (M+H)⁺.

Intermediate 13. 1-(3-Chloro-2-fluorophenyl)-1H-imidazole-4-carboxylicacid: Intermediate 13 was made in the same way as Intermediate 12 byreplacing Intermediate 12A with Intermediate 13A. MS(ESI) m/z: 241.0(M+H)⁺.

Intermediate 141-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-1H-pyrazole-4-carboxylic acid

Intermediate 14A. tert-Butyl3-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To aclear, colorless solution of 1-Boc-3-hydroxypiperidine (0.250 g, 1.242mmol), 4-ethoxycarbonyl-pyrazole (0.174 g, 1.242 mmol), andtriphenylphosphine (0.391 g, 1.491 mmol) in THF (4.97 mL) was added inportions over 5 min di-tert-butylazodicarboxylate (0.372 g, 1.615 mmol).The resulting pale yellow solution was stirred at rt overnight. Thereaction mixture was then concentrated and purified by silica gelchromatography to yield Intermediate 14A (0.0646 g, 16%) as a clear,colorless residue. MS(ESI) m/z: 268.1 (M-C₄H₈+H)⁺.

Intermediate 14.1-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-1H-pyrazole-4-carboxylic acid:To a clear, colorless solution of Intermediate 14A (0.0646 g, 0.200mmol) in MeOH (0.666 ml) was added dropwise 1.0 M sodium hydroxide(0.599 ml, 0.599 mmol). The resulting slightly cloudy reaction mixturewas stirred at rt. After 6 h, the reaction was cooled to 0° C. andneutralized with 1.0 N HCl. The mixture was concentrated to give a whitesolid. The solid was partitioned between EtOAc and 0.5 N HCl and thelayers were separated. The aqueous layer was extracted with EtOAc (2×).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated to give Intermediate 14 (0.0616 g,104%) as a white foam. MS(ESI) m/z: 240.1 (M-C₄H₈+H)⁺.

Intermediate 15 1-(3-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylicacid

Intermediate 15 was prepared in the same way as Intermediate 14. MS(ESI)m/z: 210.1 (M+H)⁺.

Intermediate 16 Methyl 4-(2-bromoacetyl)-3-nitrophenylcarbamate

Intermediate 16A. Methyl 4-iodo-3-nitrophenylcarbamate: To a cooled (0°C.), yellow suspension of 4-iodo-3-nitroaniline (8.46 g, 32.0 mmol) inDCM (320 mL) and pyridine (2.85 mL, 35.2 mmol) was added dropwise methylchloroformate (2.61 mL, 33.6 mmol) and the reaction was stirred for 1.5h. The reaction mixture was diluted with DCM and washed with saturatedNaHCO₃ solution followed by brine. The organic layer was then dried overMgSO₄, filtered and concentrated. The residue was dissolved in minimalDCM (˜100 mL), then hexane (600 mL) was added to give a yellowsuspension. The above suspension was then filtered and the solid wasrinsed with hexane and air-dried to yield the desired product as ayellow solid (10.3 g, 100%). MS(ESI) m/z: 321.3 (M−H).

Intermediate 16B. Methyl 4-acetyl-3-nitrophenylcarbamate: A solution ofIntermediate 16A (1 g, 3.11 mmol), tributyl(1-ethoxyvinyl)stannane(2.098 mL, 6.21 mmol), and bis(triphenylphosphine) palladium(II)chloride(0.218 g, 0.311 mmol) in toluene (6.21 mL) was heated at 110° C. in asealed tube. After 3 h, the reaction mixture was cooled to rt andconcentrated to dryness. The residue was then dissolved in THF (5 mL),added 1 N HCl solution (15.53 mL, 15.53 mmol), and the reaction wasstirred at rt for 1 h. The reaction mixture was diluted with EtOAc,washed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was then purified by silica gel chromatography to yieldthe desired product as a brown solid (0.544 g, 74%). MS(ESI) m/z: 239.3(M+H)⁺.

Intermediate 16. Methyl 4-(2-bromoacetyl)-3-nitrophenylcarbamate: To ayellow solution of Intermediate 16B (0.544 g, 2.284 mmol) in EtOAc(18.27 mL) was added copper (II) bromide (1.020 g, 4.57 mmol). The flaskwas equipped with a reflux condenser and then the reaction was warmed to70° C. After 3 h, the reaction was stopped and cooled to rt. Thereaction mixture was then filtered through a sintered glass funneleluting with EtOAc. The green filtrate was washed with H₂O (3×), brine,dried over Na₂SO₄, filtered and concentrated to yield the desiredproduct as a brown foam (0.724 g, 100%). MS(ESI) m/z: 317.4 (M+H)⁺,319.4 (M+2+H)⁺. The crude product was carried forward without anyfurther purification.

An alternative procedure for Intermediate 16 is highlighted here.

Alternative Intermediate 16B. Methyl4-(1-ethoxyvinyl)-3-nitrophenylcarbamate: A solution of Intermediate 16A(1 g, 3.11 mmol), tributyl(1-ethoxyvinyl)stannane (1.574 mL, 4.66 mmol)and bis(triphenylphosphine)palladium(II) chloride (0.109 g, 0.155 mmol)in toluene (6.21 mL) in a round bottom flask equipped with a condenserwas heated at 110° C. After 2 h, the reaction was cooled to rt, filteredthrough a 0.45μ GMF filter and rinsed with EtOAc. The filtrateconcentrated to dryness and purified by silica gel chromatography toobtain the desired product as a brown solid (0.56 g, 68%). MS(ESI) m/z:267.3 (M+H)⁺.

Alternative Intermediate 16. (Reference: J. Med. Chem., 45:2127-2130(2002)) To a solution of alternative intermediate 16B (0.56 g, 2.103mmol) in THF (3.12 mL) and H₂O (1.091 mL) was added NBS (0.374 g, 2.103mmol). After stirring at rt for 20 min, the reaction mixture waspartitioned between EtOAc and brine. The organic layer was then driedover Na₂SO₄, filtered, and concentrated to yield the desired product asa yellow oil (0.667 g, 100%). MS(ESI) m/z: 317.2 (M+H)⁺, 319.2 (M+2+H)⁺.

Intermediate 17 Benzyl 2-methylbut-3-enoate

Intermediate 17. Benzyl 2-methylbut-3-enoate: To a solution of2-methylbut-3-enoic acid (9.5 g, 95 mmol) in DCM (80 mL) was addedphenylmethanol (10.26 g, 95 mmol),N,N′-methanediylidenedicyclohexanamine (19.58 g, 95 mmol) and DMAP(1.159 g, 9.49 mmol) (exothermic reaction) and the reaction was stirredat rt over weekend. The reaction mixture was filtered through a pad ofCELITE® to remove the solids and the filtrate was concentrated. Theresidue was purified by silica gel chromatography to yield the desiredproduct as a colorless oil.

Intermediate 18 [3-Bromo-4-(2-bromo-acetyl)-phenyl]-carbamic acid methylester

Intermediate 18A. 2-Bromo-4-nitro-benzoic acid: To a warm (80° C.)solution of pyridine (500 mL) and water (1 L) was added 4-nitro-2-bromotoluene (100 g, 0.46 mol). The resulting suspension was stirred until itbecame a clear solution. To the above reaction mixture was then addedKMnO₄ (600 g, 3.8 mol) in portions over 1.5 h and stirring was continuedovernight. The reaction mixture was then cooled to rt and then 10%aqueous NaOH (200 mL) was added. After 15 min, the reaction was filteredand the solid was rinsed with 10% aqueous NaOH (5×100 mL). The filtratewas extracted with MTBE (3×250 mL). The clear aqueous layer was cooledto 10° C. and then it was acidified with concentrated HCl. The aqueouslayer was again extracted with MTBE (4×500 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated toafford 72 g of Intermediate 18A. ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d,J=8 Hz, 1H), 8.28-8.48 (m, 1H), 8.49 (d, J=2.4 Hz, 1H), 14.1 (br. s, 1H)ppm.

Intermediate 18B. 2-(2-Bromo-4-nitro-benzoyl)-malonic acid diethylester: To a solution of Intermediate 18A (50 g, 0.2 mol) in toluene (500mL) was added TEA (24.6 g, 0.24 mol). The reaction was cooled to 15° C.and ethyl chloroformate (24 g, 0.22 mol) was added. After 45 min, themixed anhydride solution was cooled to 0° C. In a separate flask: To asuspension of Mg turnings (5.4 g) in dry ether (300 mL) was added EtOH(3.0 mL), CCl₄ (2.0 mL), and diethyl malonate (34 mL, 0.22 mol). Themixture was stirred at 40° C. for an hour to ensure that the magnesiumdissolved completely. After the reaction became a clear solution, it wasadded to the cooled solution of the mixed anhydride. After 2 h, thereaction was quenched with 2 N sulfuric acid (200 mL) and then extractedwith EtOAc (4×100 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated to afford 80 g ofIntermediate 18B. This was used in the next step without furtherpurification.

Intermediate 18C. 1-(2-Bromo-4-nitro-phenyl)-ethanone: A mixture ofIntermediate 18B (80 g, 0.2 mol) in acetic acid (400 mL) and sulfuricacid (400 mL) was stirred at 105° C. After 3 h, the reaction mixture wascooled to rt and then extracted with ethyl acetate (2×500 mL). Thecombined organic layers were washed with 20% aqueous NaOH solution,dried over sodium sulfate, filtered and concentrated to give 43.0 g ofIntermediate 18C. ¹H NMR (400 MHz, CDCl₃) δ 2.66 (s, 3H), 7.57 (d, J=8Hz, 1H), 8.21-8.24 (dd, 1H), 8.48 (d, J=2.0 Hz, 1H) ppm.

Intermediate 18D. 1-(4-Amino-2-bromophenyl)ethanone: To a solution ofIntermediate 18C (19 g, 0.077 mol) in EtOH (400 mL) was added inportions tin(II) chloride (74 g, 0.39 mol). Following the addition, thereaction was heated to refluxing temperature overnight. The reactionmixture was then concentrated and the residue was dissolved in 10%aqueous NaOH (200 mL). The aqueous solution was extracted with ethylacetate (2×200 mL). The combined organic layers were washed with brineand concentrated to afford an oil. Petroleum ether (25 mL) was added tothe oil to afford a suspension that was decanted and the solid wassuspended in 20% ethyl acetate/petroleum ether. The organic layer wasfiltered and the solids were collected to afford 14 g of Intermediate18D.

Intermediate 18E. (4-Acetyl-3-bromo-phenyl)-carbamic acid methyl ester:To a cooled (10° C.) mixture of Intermediate 18D (14 g, 0.065 mol) andHunig's base (12.7 g, 0.098 mol) in dry dioxane (140 mL) was addedmethyl chloroformate (7.4 g, 0.078 m) dropwise. After 3 h, the reactionmixture was quenched with water (100 mL) and then extracted with ethylacetate (2×150 mL). The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated. Purification bytrituration from isopropanol provided 14 g of Intermediate 18E. MS(ESI)m/z: 271.7 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) 2.50 (s, 3H), 3.71 (s, 3H),7.53-7.56 (m, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 10.14(s, 1H) ppm.

Intermediate 18. [3-Bromo-4-(2-bromo-acetyl)-phenyl]-carbamic acidmethyl ester: To a cooled (10° C.) solution of Intermediate 18E (90 g,0.33 mol) in dry dioxane (900 mL) was added a solution of bromine (52.9g, 0.33 mol) in dioxane (430 mL) dropwise over 1 h. After 2 h, ice coldwater (500 mL) was added and the reaction was extracted with ethylacetate (2×500 mL). The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated to afford 110 g ofcrude product. A suspension of the crude product in EtOH (1 L) waswarmed to 50° C. After a clear solution had formed, water (1.0 L) wasadded dropwise and the mixture was gradually cooled to 35° C. Theprecipitated solid was collected by filtration, washed with EtOH (200mL), air-dried, and then dried at 50° C. under vacuum for 30 min toyield 70 g of Intermediate 18.

Intermediate 19 5-Amino-1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylicacid

Intermediate 19A. Ethyl5-amino-1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylate: A mixture of(2,3-dichlorophenyl)hydrazine, HCl (1 g, 4.68 mmol), (E)-ethyl2-cyano-3-ethoxyacrylate (0.792 g, 4.68 mmol), and K₂CO₃ (0.647 g, 4.68mmol) in EtOH (10 mL) was added to a microwave vial and was heated at85° C. for 20 h. The reaction mixture was then cooled to rt and thenpoured into ice-water. The suspension formed was then filtered and thesolid was rinsed with water and dried in a vacuum oven (50° C.) for 4 hto afford a brown solid. The crude product was then purified by silicagel chromatography to yield a brown solid as ethyl5-amino-1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylate (0.93 g, 66%yield). MS(ESI) m/z: 300.0 (M+H)⁺.

Intermediate 19. 5-Amino-1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylicacid: A clear yellow solution of Intermediate 19A (0.026 g, 0.087 mmol)in MeOH (2 mL) and 1.0 N NaOH (0.260 mL, 0.260 mmol) was stirred at rtfollowed by heating to 70° C. for 24 h. To the mixture was addedadditional 1 N NaOH (0.260 ml, 0.260 mmol), and the reaction mixture waswarmed to 90° C. for 7 h. The reaction mixture was cooled to rt, and 1 NHCl (0.75 mL) was added and the reaction mixture was concentrated toafford a yellow solid as5-amino-1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (0.065 g,99%). MS(ESI) m/z: 271.9 (M+H)⁺.

Intermediate 20 1-(2,3-Dichlorophenyl)-1H-pyrazole-4-carboxylic acid

Intermediate 20A. Ethyl1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylate: To a solution ofIntermediate 19A (0.23 g, 0.766 mmol) in THF (8 mL) was added isoamylnitrite (0.206 mL, 1.533 mmol) and the reaction was heated in amicrowave vial at 80° C. After 16 h, the reaction mixture was cooled tort and concentrated. The crude product was then purified by silica gelchromatography to afford a yellow gummy oil as ethyl1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylate (0.187 g, 86%). MS(ESI)m/z: 285.0 (M+H)⁺.

Intermediate 20. 1-(2,3-Dichlorophenyl)-1H-pyrazole-4-carboxylic acid:To a clear yellow solution of Intermediate 20A (0.187 g, 0.656 mmol) inMeOH (8 mL) was added 1.0 N NaOH (1.968 mL, 1.968 mmol) and the reactionmixture was stirred at rt. After 18 h, the reaction mixture wasconcentrated to remove MeOH. To the above crude product was then addedwater to afford a yellow solution. To this solution was then added 1 NHCl (2.5 mL) to afford a white suspension which was filtered and thesolid was rinsed with water, and then dried in a vacuum oven (50° C.)for 4 h. A yellow solid was obtained as1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (0.16 g, 95%).MS(ESI) m/z: 257.0 (M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 8.51 (s, 1H), 8.13(s, 1H), 7.75 (dd, J=8.3, 1.7 Hz, 1H), 7.61-7.56 (m, 1H), 7.54-7.49 (m,1H) ppm.

Intermediate 211-(3-Chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 21.1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylicacid: To a solution of 3-chloro-2-fluoroaniline (1.7 g, 11.68 mmol) inTFA (10 mL) was added water (2 mL) and the reaction mixture was cooledto 0° C. To the above solution was then added sodium nitrite (0.806 g,11.68 mmol) over 0.5 h. To the above mixture was then added slowly asolution of sodium azide (1.928 g, 29.7 mmol) in water. The reactionmixture was then stirred at 0° C. for 10 min, and then allowed to warmto rt. After 2 h, the reaction mixture was quenched by addition of water(100 mL) and the insoluble solids from the reaction mixture werefiltered and dried under suction in the presence of nitrogen. To theazide was then added methyl acetoacetate (1.492 g, 12.85 mmol) in MeOH(12 mL) and methanol, sodium derivative (2.78 g, 12.85 mmol) and themixture was heated at 65° C. in a sealed tube overnight. The reactionmixture was cooled to rt and then to 0° C. followed by addition of THF(50 mL). To the above mixture was then added NaOH (58.4 mL, 58.4 mmol),and the reaction was warmed to 50° C. After 2 h, the organics wereconcentrated and the remaining aqueous layer was acidified with 1.0 MHCl solution. The resulting suspension was filtered and the solids werewashed with water followed by a small amount of cold MeOH and dried inan oven overnight (50° C.) to give1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid(1.86 g, 62%) as an off-white solid. MS(ESI) m/z: 256.0 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 7.99-7.89 (m, 1H), 7.80-7.71 (m, 1H), 7.53 (td,J=8.2, 1.3 Hz, 1H), 2.44 (s, 3H) ppm.

Intermediate 222-(3-Chloro-2,6-difluorophenyl)-1H-imidazole-4-carboxylic acid

Intermediate 22A.2-(3-Chloro-2,6-difluorophenyl)-4-(trifluoromethyl)-1H-imidazole:(Reference: WO 2008/050244) To a solution of potassium acetate (0.872 g,8.88 mmol) in H₂O (3 mL) was added3,3-dibromo-1,1,1-trifluoropropan-2-one (1.098 g, 4.07 mmol). The abovereaction mixture was then heated at 100° C. for 0.5 h. The reactionmixture was then cooled to rt and to the mixture was then added asolution of 3-chloro-2,6-difluorobenzaldehyde (0.653 g, 3.7 mmol) inMeOH (4 mL) and THF (4 mL), followed by concentrated NH₄OH (8 mL). Themixture was stirred overnight at rt. The reaction mixture was extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo to yield2-(3-chloro-2,6-difluorophenyl)-4-(trifluoromethyl)-1H-imidazole (0.95g, 91%). MS(ESI) m/z: 283.0 (M+H)⁺.

Intermediate 22.2-(3-Chloro-2,6-difluorophenyl)-1H-imidazole-4-carboxylic acid: Asolution of Intermediate 22A (0.95 g, 3.36 mmol) in 5 N aqueous NaOH (10mL) solution was heated at 90° C. for 2 h. The reaction mixture was thencooled to rt, neutralized carefully to pH=6-7 and extracted with1-butanol (3×30 mL) to provide2-(3-chloro-2,6-difluorophenyl)-1H-imidazole-4-carboxylic acid (0.57 g,66%). MS(ESI) m/z: 259.0 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ 7.66-7.55 (m,H), 7.60 (s, 1H), 7.16 (td, J=9.2, 1.8 Hz, 1H) ppm.

Intermediate 235-Amino-1-(5-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid

Intermediate 23A. Ethyl5-amino-1-(5-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate: A brownsuspension of (5-chloro-2-fluorophenyl)hydrazine hydrochloride (0.500 g,2.54 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.472 g, 2.79 mmol) inEtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was warmed to 85° C. After5 h, the reaction was stopped, cooled to rt, and concentrated to give abrown solid. Purification by normal phase chromatography providedIntermediate 23A (0.244 g, 34%) as a thick, viscous orange oil. MS(ESI)m/z: 284.0 (M+H)⁺.

Intermediate 23.5-Amino-1-(5-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid: Acloudy, yellow suspension of Intermediate 23A (0.125 g, 0.441 mmol) inMeOH (2.203 mL) and 1.0 N NaOH (1.763 mL, 1.763 mmol) was warmed to 50°C. After 8 h, the reaction mixture was cooled to rt and the clear,yellow orange solution was concentrated to give a yellow solid. Theyellow solid was dissolved in water and 1.0 N HCl was added to give awhite suspension (pH 3-4). The mixture was then extracted with EtOAc(2×). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated to give Intermediate 23 (0.096 g,85%) as an off-white solid. MS(ESI) m/z: 256.0 (M+H)⁺ and 258.0(M+2+H)⁺.

Intermediate 241-(3-Chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid, HCl

Intermediate 24A. Ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylate: Using amodified procedure of Sreedhar. (Reference: Sreedhar, B., Synthesis, 795(2008)). To a suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate(0.530 g, 3.44 mmol) and (3-chloro-2-fluorophenyl)boronic acid (0.500 g,2.87 mmol) in MeOH (5.74 mL) was added cuprous oxide (0.041 g, 0.287mmol). The resulting purple suspension was stirred vigorously under anatmosphere of air (drying tube used). After 20 h, the reaction mixturewas filtered to remove the solids and the clear blue filtrate wasconcentrated to give a blue solid. The blue solid was suspended in DCMand filtered to remove the solids and the blue filtrate was concentratedto give a pale blue solid weighing 0.187 g. Purification by normal phasechromatography gave ethyl1-(3-chloro-2-fluorophenyl)-4-methyl-1H-imidazole-5-carboxylate (0.0187g, 2%) as a clear, colorless residue and ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylate(Intermediate 24A) (0.0079 g, 1%) as a clear, colorless residue. MS(ESI)m/z: 283.1 (M+H)⁺.

Intermediate 24A can also be synthesized in three steps according to thefollowing sequence:

Intermediate 24A1. Ethyl3-(3-chloro-2-fluorophenyl)amino)-2-nitrobut-2-enoate: Using a modifiedprocedure described by Gomez-Sanchez. (Reference: Gomez-Sanchez, A. etal., Anales De Quimica, 81(2):139 (1985).) A clear, faint yellowsolution of ethyl nitroacetate (4.17 ml, 37.6 mmol) andtriethylorthoacetate (6.93 mL, 37.6 mmol) in toluene (9.39 mL) washeated to 110° C. A Dean-Stark trap was used to azeotrope the ethanol.Approximately every 30 min, the solvent was removed from the Dean-Starkand additional toluene (6 mL) was added to the reaction flask. Over thecourse of the reaction the color became a clear, dull yellow color.After 7.5 h, the reaction was stopped and it was cooled to rt. Excesssolvent and starting materials were removed by distillation (5 mm Hg at100° C.) leaving ethyl 3-ethoxy-2-nitrobut-2-enoate (5.46 g) as anorange liquid. An orange solution of 3-chloro-2-fluoroaniline (5.86 g,40.2 mmol) and ethyl 3-ethoxy-2-nitrobut-2-enoate (5.45 g, 26.8 mmol) inethanol (13.41 mL) was stirred at rt. After 7 h, the reaction wasstopped and concentrated to give an orange oil. The orange oil wasdiluted with EtOAc and washed with 1.0 N HCl (2×), saturated NaHCO₃,brine, dried over sodium sulfate, filtered and concentrated to give anorange oil. Purification by normal phase chromatography gaveIntermediate 24A1 (2.90 g, 36%) as a viscous orange-yellow oil. ¹H NMRindicated a 1:1 E:Z mixture. MS(ESI) m/z: 325.0 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 11.54 (br. s., 1H), 10.77 (br. s., 1H), 7.50-7.45 (m, 1H),7.44-7.38 (m, 1H), 7.24-7.12 (m, 4H), 4.39 (q, J=7.2 Hz, 2H), 4.34 (q,J=7.2 Hz, 2H), 2.15 (d, J=1.4 Hz, 3H), 2.12 (d, J=1.4 Hz, 3H), 1.39 (t,J=7.2 Hz, 3H), 1.36 (t, J=7.0 Hz, 3H).

Intermediate 24A (Alternative). Ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylate: Using amodified procedure described by Gomez-Sanchez. (Reference:Gomez-Sanchez, A. et al., J. Heterocyclic Chem., 24:1757 (1987).) Aclear, yellow solution of Intermediate 24A1 (2.90 g, 9.58 mmol) intriethylorthoformate (96 mL) was degassed with argon for 20 min. Next,platinum on carbon (0.935 g, 0.479 mmol) was added. The flask wasequipped with a reflux condenser and the reaction was purged withhydrogen (balloon) for several minutes. The reaction was stirred under ahydrogen atmosphere and the reaction was warmed to 75° C. After a totalof 4 h, the reaction was cooled to rt. The reaction was placed undervacuum for several minutes and then backfilled with argon. The processwas repeated a total of 5 times. Next, CELITE® was added and thereaction was filtered, washing with ethanol. The filtrate wasconcentrated to give a clear, yellow-brown oil weighing 3.17 g.Purification by normal phase chromatography provided Intermediate 24A(Alternative) (1.64 g, 61%) as a white solid. MS(ESI) m/z: 283.0 (M+H)⁺.¹H NMR (500 MHz, methanol-d₄) δ 7.82 (d, J=0.8 Hz, 1H), 7.73 (ddd,J=8.3, 6.7, 1.8 Hz, 1H), 7.48 (ddd, J=8.0, 6.5, 1.7 Hz, 1H), 7.43-7.38(m, 1H), 4.36 (q, J=7.2 Hz, 2H), 2.39 (d, J=1.1 Hz, 3H), 1.39 (t, J=7.2Hz, 3H).

Intermediate 24.1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid, 1HCl: To a clear, colorless solution Intermediate 24A (Alternative) (1.64g, 5.80 mmol) in methanol (29.0 ml) was added 1.0 M NaOH (17.40 mL,17.40 mmol). The reaction was stirred at rt. After 20 h, the reactionwas concentrated under high vacuum with minimal heating to give a whitesolid. The solid was suspended in water and 1.0 N HCl was added untilthe mixture was at a pH=1-2. The solid was collected by filtration andrinsed with water, air-dried, and dried under high vacuum to giveIntermediate 24 (1.44 g, 81%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 7.91 (d, J=0.5 Hz, 1H), 7.83 (ddd, J=8.3, 6.9, 1.7 Hz, 1H),7.63 (td, J=7.5, 1.5 Hz, 1H), 7.46 (td, J=8.1, 1.4 Hz, 1H), 2.32 (s,3H). MS(ESI) m/z: 255.0 (M+H)⁺ and 257.0 (M+2+H)⁺.

Intermediate 251-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

Intermediate 25A. Ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate:(Reference: Herold, P. et al., Tetrahedron, 56:6497-6499 (2000)) Asolution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g,2.79 mmol), (3-chloro-2-fluorophenyl)hydrazine hydrochloride (0.500 g,2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirredat rt. After 10 min, the reaction mixture was concentrated and purifiedby silica gel chromatography. The desired product, ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (200 mg,28%), was obtained as an off white solid. MS(ESI) m/z: 283.1 (M+H)⁺.

Intermediate 25.1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid: To asolution of Intermediate 25A (50 mg, 0.177 mmol) in MeOH (0.884 mL) wasadded 1 N NaOH (aqueous) (1.061 mL, 1.061 mmol) and the reaction wasstirred at 50° C. in a sealed vial for 3 h. The reaction mixture wasthen cooled to rt and concentrated. The residue was then partitionedbetween 1 N HCl (aqueous) and EtOAc. The layers were separated and theaqueous layer was extracted with EtOAc. The organic layers werecombined, washed with brine, and concentrated to give Intermediate 25 asan off-white solid (48 mg, 107%). MS(ESI) m/z: 255.0 (M+H)⁺.

Intermediate 261-(3-Chloro-2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylicacid

Intermediate 26A. 2-Azido-4-chloro-1,3-difluorobenzene: To a solution of3-chloro-2,6-difluoroaniline (1.7 g, 10.39 mmol) in TFA (10 mL) andwater (2 mL) at 0° C. was added sodium nitrite (0.717 g, 10.39 mmol)over a period of 0.5 h. After completion of addition, sodium azide(1.716 g, 26.4 mmol) in water (5 mL) was added dropwise. The reactionmixture was stirred at 0° C. for 10 min and then allowed to warm to rt.The reaction was diluted with water (75 mL) and extracted with EtOAc.The organic layer was dried and concentrated to give the desired product(1.16 g, 56%) as a brown solid.

Intermediate 26B. Methyl1-(3-chloro-2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate:The mixture of Intermediate 26A (1.16 g, 6.12 mmol), methyl3-oxobutanoate (0.729 mL, 6.73 mmol), NaOMe (1.539 mL, 6.73 mmol), andMeOH (12 mL) in a microwave vial was stirred at 65° C. overnight. Thereaction was concentrated and purified by silica gel chromatography toisolate the desired product (46 mg, 2%) as a yellow solid. MS(ESI) m/z:287.8 (M+H)⁺.

Intermediate 26.1-(3-Chloro-2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylicacid: To a solution of Intermediate 26B (46 mg, 0.160 mmol) was addedLiOH (0.320 mL, 0.320 mmol). The reaction was stirred at rt overnightand acidified with 1 N HCl. The mixture was extracted with EtOAc. Theorganic layer was dried and concentrated to yield the desired product(40 mg, 82%). MS(ESI) m/z: 274.0 (M+H)⁺.

Intermediate 275-Amino-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 27A. Ethyl5-amino-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate:(PCT International Application No. 2006/047516 (2006)) To a solution ofNaOEt (4.99 g, 15.39 mmol) in EtOH (10 mL) at 0° C. was added ethyl2-cyanoacetate (1.501 ml, 14.11 mmol). The reaction was stirred at 0° C.for 10 min and added 1-azido-3-chloro-2-fluorobenzene (2.2 g, 12.82mmol). The reaction was allowed to slowly warm up to rt and stirred for14 h. The mixture was treated with water (3 mL) and extracted with EtOAc(3×30 mL). The combined extracts were concentrated and purified bysilica gel chromatography to yield the desired product (2.1 g, 58%).MS(ESI) m/z: 285.1 (M+H)⁺.

Intermediate 27.5-Amino-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid:To a solution of Intermediate 27A (100 mg, 0.351 mmol) in THF (15 mL)and MeOH (15.0 mL) was added NaOH (70 mg, 1.756 mmol). The reaction wasstirred at 50° C. for 2 h and then concentrated. The mixture wasacidified to pH˜5 with 1 N HCl. The resulting solid was filtered anddried to yield the desired product (69 mg, 77%). MS(ESI) m/z: 257.0(M+H)⁺.

Intermediate 285-Chloro-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 28A. Ethyl5-chloro-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate:(Can. J. Chem., 37:118-119 (1959)). To a solution of Intermediate 27A(1.1 g, 3.86 mmol) in EtOH (30 mL) at 0° C. was passed HCl gas until allof the solid dissolved. To the solution was added isoamyl nitrite (0.520mL, 3.86 mmol) in one portion and the resulting solution was kept at0-5° C. for 48 h. The reaction mixture was diluted in EtOAc and washedwith aq NaHCO₃ and brine. The organic layer was concentrated andpurified by reverse phase HPLC to yield the desired product. MS(ESI)m/z: 304.0 (M+H)⁺.

Intermediate 28.1-(3-Chloro-2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylicacid: To a solution of Intermediate 28A (50 mg, 0.164 mmol) in THF (6mL) and MeOH (3.00 mL) was added LiOH (39.4 mg, 1.644 mmol). Thereaction was stirred at rt for 1 h and concentrated. The residue waspurified by reverse phase HPLC to yield Intermediate 28 (23 mg, 51%).MS(ESI) m/z: 276.0 (M+H)⁺.

Intermediate 291-(3-Chloro-2-fluorophenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylicacid

Intermediate 29.1-(3-Chloro-2-fluorophenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylicacid: To a solution of Intermediate 28A (50 mg, 0.164 mmol) in THF (6mL) and MeOH (3.00 mL) was added LiOH (39.4 mg, 1.644 mmol). Thereaction was stirred at rt for 1 h and concentrated. The residue waspurified by reverse phase HPLC to yield Intermediate 29 (12 mg, 27%).MS(ESI) m/z: 272.0 (M+H)⁺.

Intermediate 301-(2-Fluoro-3-methoxyphenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylicacid

Intermediate 30.1-(3-Chloro-2-fluorophenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylicacid: To a solution of 2-fluoro-3-methoxyaniline (1 g, 7.09 mmol) in TFA(10 mL) and water (5 mL) at 0° C. was added an aq. solution of NaNO₂(0.733 g, 10.63 mmol) dropwise. The resulting mixture was stirred at 0°C. for 0.5 h and NaN₃ (0.921 g, 14.17 mmol) was added portionwise. Thereaction mixture was gradually warmed to rt and stirred for 4 h. Thereaction was quenched with water (150 mL) and extracted with EtOAc(2×100 mL). The organic layer was washed with sodium phosphate solution(10%) and brine (50 mL), dried, and concentrated. The resulting brownoil was re-dissolved in DMSO (20 mL) and added t-butylpropiolate (1 mL)followed by K₂CO₃ (1 g), Cu(OAc)₂ (0.2 g), and sodium ascorbate (100mg). The resulting mixture was stirred at rt overnight. The reaction wasquenched with water (200 mL) and extracted with EtOAc (2×100 mL). Theorganic layer was dried and concentrated. The residue was purified bysilica gel chromatography to yield the desired product as brown oil. ¹HNMR (400 MHz, CDCl₃) δ 13.19 (br. s., 1H), 7.36-7.20 (m, 2H), 7.17-6.95(m, 1H), 6.76 (td, J=8.1, 1.3 Hz, 1H), 3.91 (s, 3H), 1.74-1.49 (m, 10H).MS(ESI) m/z: 238.0 (M+H)⁺.

Intermediate 31 1-(Thiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 31. 1-(Thiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid:To a suspension of methyl1-(thiazol-2-yl)-1H-1,2,3-triazole-4-carboxylate (7.4 mg, 0.035 mmol)(prepared as in J. Heterocyclic Chem., 42:1167 (2005)) in MeOH (352 μL)was added 1 N NaOH (141 μL, 0.141 mmol). The reaction became clearwithin 5 min. The reaction was concentrated. The resulting residue waspartitioned between 1 N HCl and EtOAc. The layers were separated and theaqueous layer was extracted with EtOAc (2×). The organic layers werecombined, washed with brine, dried over MgSO₄, filtered and concentratedto yield the desired product (5 mg, 72%) as a white solid. MS(ESI) m/z:169.9 (M+H)⁺.

Intermediate 323-Acetyl-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylicacid

Intermediate 32A.(E)-N′-(3-Chloro-2-fluorophenyl)-2-oxopropanehydrazonoyl chloride: To asolution of 3-chloro-2-fluoroaniline (1.511 mL, 13.74 mmol) in HCl (116mL, 116 mmol) at 0° C. was added a solution of sodium nitrite (1.896 g,27.5 mmol) in water (12 mL) dropwise while maintaining the temperatureat 0° C. After completion of addition, the reaction was stirred at thesame temperature for additional 30 mins. The pH of the reaction mixturewas adjusted to 4.5 using solid sodium acetate. The resultant mixturewas then treated dropwise with 3-chloropentane-2,4-dione (2.129 mL,17.86 mmol) in methanol (12 mL). After completion of addition, thereaction mixture was allowed to warm to room temperature and stirred atroom temperature overnight. The reaction mixture was diluted with waterand then extracted with ether. The crude product was then purified bysilica gel chromatography to isolate the desired product. MS(ESI) m/z:249.0 (M+2H)⁺.

Intermediate 32B. Ethyl3-acetyl-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate:To a solution (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate (36.8 mg, 0.201mmol) in DCM (2 mL) was added DIEA (0.168 mL, 1.204 mmol) followed by32A (50 mg, 0.201 mmol) and the reaction was stirred at refluxingtemperatures overnight. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over MgSO₄ andconcentrated to give the crude product. The crude product was thenpurified using an ISCO normal phase system. MS(ESI) m/z: 325.0 (M+H)⁺.

Intermediate 32.3-Acetyl-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylicacid: To a solution of 32B (67 mg, 0.206 mmol) in THF (2 mL) was addedLiOH (0.227 mL, 0.227 mmol) and the reaction was stirred at roomtemperature overnight. The reaction mixture was acidified with 1 N HCland extracted with EtOAc. The crude product was taken to the next stepwithout further purification. MS(ESI) m/z: 297.0 (M+H)⁺.

Intermediate 331-(3-Chloro-2-fluorophenyl)-3-hydroxy-1H-pyrazole-4-carboxylic acid

Intermediate 33A. N′-(3-Chloro-2-fluorophenyl)acetohydrazide: To asolution of (3-chloro-2-fluorophenyl)hydrazine, HCl (450 mg, 2.284 mmol)in ether (10 mL) and THF (1 mL) at 0° C. was added sodium hydroxide(0.228 mL, 2.284 mmol) and stirred at room temperature for 1 h. Thereaction mixture was concentrated, diluted with EtOAc and washed withbrine. The crude product was then dried under vacuum and taken to thenext step. To a solution of the above obtained oil in ether (10 mL) at0° C. was added dropwise a solution of acetic anhydride (0.215 mL, 2.284mmol) in ether (5 mL) and stirred at 0° C. for 30 min. The reactionmixture was concentrated, diluted with ethyl acetate and washed withbrine. The organic layer was dried over MgSO₄ and concentrated to yieldthe crude product. The crude product was then taken to the next stepwithout further purification. MS(ESI) m/z: 203.1 (M+H)⁺.

Intermediate 33B. Ethyl1-(3-chloro-2-fluorophenyl)-3-hydroxy-1H-pyrazole-4-carboxylate: ToIntermediate 33A (261 mg, 1.288 mmol) was added phosphoryl trichloride(973 μL, 10.43 mmol) followed by diethyl 2-(ethoxymethylene)malonate(351 μL, 1.739 mmol) and the resulting solution was heated at 70° C. forovernight. To the reaction mixture was added water slowly (Caution: lotof heat generated) and allowed to stir until the reaction mixture cooledback to room temperature. The crude product was then diluted with ethylacetate and washed with brine. The organic layer was dried over MgSO₄and concentrated to yield the crude product which was then purifiedusing silica gel chromatography. MS(ESI) m/z: 285.0 (M+H)⁺.

Intermediate 33.1-(3-Chloro-2-fluorophenyl)-3-hydroxy-1H-pyrazole-4-carboxylic acid: Toa solution of Intermediate 33B (52 mg, 0.183 mmol) in THF (2 mL) wasadded LiOH (0.183 mL, 0.183 mmol) and stirred at room temperatureovernight. The reaction mixture was acidified using 1 N HCl and thenextracted with EtOAc. The organic layer was dried over MgSO₄ andconcentrated to yield the crude product. The crude product was takenfurther without any further purification. MS(ESI) m/z: 257.0 (M+H)⁺.

Intermediate 341-(5-Chloro-2-cyanophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 34A. 2-Azido-4-chlorobenzonitrile: To a solution of2-amino-4-chlorobenzonitrile (2.0 g, 13.11 mmol) in TFA (12 mL) wasadded water (2.4 mL). After cooling to 0° C., sodium nitrite (0.904 g,13.11 mmol) was added over a period of 0.5 h. After this addition,sodium azide (2.164 g, 33.3 mmol) in water (5 mL) was gradually addeddropwise. The reaction was stirred at 0° C. for 10 min, and then allowedto warm to room temperature. After 2 h, quenched the reaction with water(100 mL) and insoluble solid was filtered and dried under suction andnitrogen. Aliquot LCMS analysis indicated starting material disappearedand a new peak formed which was not ionizing.

Intermediate 34.1-(5-Chloro-2-cyanophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid:To a mixture of Intermediate 34A (400 mg, 2.035 mmol) and methylacetoacetate (0.241 mL, 2.238 mmol) in MeOH (12 mL) was added NaOMe (121mg, 2.238 mmol). The mixture was heated at 65° C. in a sealed tubeovernight. The reaction mixture was quenched with brine and extracted togive the ester product. The aqueous layer was acidified and thenextracted with ethyl acetate to yield the desired hydrolyzed productwhich was used in the next step without further purification. MS(ESI)m/z: 262.9 (M+H)⁺.

Intermediate 351-(3-Chloro-2,6-difluorophenyl)-1H-imidazole-4-carboxylic acid

Intermediate 35A. Ethyl3-((3-chloro-2,6-difluorophenyl)amino)-2-nitroacrylate: A sealed, highpressure vial containing a clear, colorless solution of ethylnitroacetate (0.170 ml, 1.529 mmol), triethylorthoformate (0.255 ml,1.529 mmol), 3-chloro-2,6-difluoroaniline (0.250 g, 1.529 mmol), aceticacid (0.026 ml, 0.459 mmol), and EtOH (1.529 ml) was heated to 70° C.After 92 h, the clear, dark yellow solution was concentrated to give anorange oil. Purification by normal phase chromatography gaveIntermediate 35A (0.0721 g, 15%) as a yellow solid. MS(ESI) m/z: 307.0(M+H)⁺.

Intermediate 35B. Ethyl1-(3-chloro-2,6-difluorophenyl)-1H-imidazole-4-carboxylate: Intermediate35B (0.029 g, 43%) was prepared according to the procedure described forIntermediate 24A (Alternative), by replacing Intermediate 24A1 withIntermediate 35A. MS(ESI) m/z: 287.1 (M+H)⁺.

Intermediate 35.1-(3-Chloro-2,6-difluorophenyl)-1H-imidazole-4-carboxylic acid:Intermediate 35 (0.0246 g, 94%) was prepared according to the proceduredescribed for Intermediate 24, by replacing Intermediate 24A(Alternative) with Intermediate 35B. MS(ESI) m/z: 259.0 (M+H)⁺.

Intermediate 363-(3-Chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboxylic acid

¹H NMR (500 MHz, MeOD) δ 7.72 (ddd, J=8.0, 6.5, 1.7 Hz, 1H), 7.60-7.56(m, 1H), 7.24 (td, J=8.0, 1.1 Hz, 1H), 5.22 (dd, J=11.8, 6.9 Hz, 1H),3.84-3.76 (m, 1H), 3.71-3.64 (m, 1H).

Intermediate 371-(3-Chloro-2-fluorophenyl)-2-methyl-1H-imidazole-4-carboxylic acid, HCl

Intermediate 37A. Ethyl3-((3-chloro-2-fluorophenyl)amino)-2-nitroacrylate: Intermediate 37A(0.563 g, 52%) was prepared according to the procedure described forIntermediate 35A, by replacing 3-chloro-2,6-difluoroaniline with3-chloro-2-fluoroaniline. MS(ESI) m/z: 289.0 (M+H)⁺.

Intermediate 37B. Ethyl1-(3-chloro-2-fluorophenyl)-2-methyl-1H-imidazole-4-carboxylate, TFA:Intermediate 37B was prepared according to the procedure described forIntermediate 24A (Alternative), by replacing Intermediate 24A1 withIntermediate 37A, by replacing triethylorthoformate withtriethylorthoacetate, and by running the reaction for 45 min.Purification by reverse phase chromatography gave Intermediate 37B(0.027 g, 17%). MS(ESI) m/z: 283.1 (M+H)⁺.

Intermediate 37.1-(3-Chloro-2-fluorophenyl)-2-methyl-1H-imidazole-4-carboxylic acid,HCl: Intermediate 37 (0.0175 g, 88%) was prepared according to theprocedure described for Intermediate 24, by replacing Intermediate 24A(Alternative) with Intermediate 37B. MS(ESI) m/z: 254.9 (M+H)⁺.

Intermediate 381-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

Intermediate 38A. Ethyl1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylate:Intermediate 38A (0.472 g, 67%) was prepared according to the proceduredescribed for Intermediate 25, by replacing(3-chloro-2-fluorophenyl)hydrazine hydrochloride with(5-chloro-2-methoxyphenyl)hydrazine hydrochloride. MS(ESI) m/z: 295.1(M+H)⁺.

Intermediate 38.1-(5-Chloro-2-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid:Intermediate 38 (0.075 g, 73%) was prepared according to the proceduredescribed for Intermediate 24, by replacing Intermediate 24A(Alternative) with Intermediate 38A. MS(ESI) m/z: 267.0 (M+H)⁺ and 269.0(M+2+H)⁺.

Intermediate 391-(5-Chloro-2-hydroxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

Intermediate 39.1-(5-Chloro-2-hydroxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid: Toa cooled (0° C.), clear yellow solution of Intermediate 38A (0.100 g,0.339 mmol) in DCM (3.39 mL) was added dropwise boron tribromide (0.321ml, 3.39 mmol). The resulting clear light green solution was stirred at0° C. for 30 min and then the reaction was allowed to warm to rt. After45 min, the reaction was added dropwise to a vigorously stirred mixtureof cold EtOAc and NaHCO₃. After the addition, the mixture was stirredvigorously for 10 min. Then, the layers were separated and the aqueouslayer was extracted with EtOAc. The organic layers were combined, washedwith brine, dried over sodium sulfate, filtered and concentrated to givethe phenol (0.105 g) as an orange residue. MS(ESI) m/z: 281.0 (M+H)⁺ and283.0 (M+2H)⁺. To a clear, yellow orange solution of the phenol inmethanol (2 mL) was added 1.0 M NaOH (2.036 mL, 2.036 mmol). Theresulting clear, burgundy solution was stirred overnight at RT. Thereaction was warmed to 50° C. for 2.5 h. The reaction was cooled to rtand concentrated. The residue was partitioned between water and EtOAcand the layers were separated. The aqueous layer was extracted withEtOAc. The aqueous layer was acidified with 1.0 M HCl and then this wasextracted with EtOAc (2×). The organic layers, following acidification,were combined and washed with brine, dried over sodium sulfate, filteredand concentrated to give Intermediate 39 (0.0657 g, 77%) as anorange-brown solid. MS(ESI) m/z: 253.0 (M+H)⁺ and 254.9 (M+2H)⁺.

Intermediate 403-Amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid

Intermediate 40A.(E)-1-Benzylidene-2-(3-chloro-2-fluorophenyl)hydrazine: Using a modifiedprocedure described by Deprez-Poulain. (Deprez-Poulain, R. et al.,European Journal of Medicinal Chemistry, 46:3867 (2011).) To a clear,orange brown solution of (3-chloro-2-fluorophenyl)hydrazine, HCl (3 g,15.23 mmol) in methanol (60.9 ml) was added benzaldehyde (1.543 mL,15.23 mmol) followed by the slow addition of 1.0 M NaOH (15.23 mL, 15.23mmol). The resulting dark brown solution was stirred at rt. Over time, aprecipitate formed. After 2.5 h, the reaction was stopped and the solidwas collected by filtration. The solid was washed with water, air-dried,and dried under vacuum overnight to give Intermediate 40A (1.01 g, 27%)as an off-white solid. MS(ESI) m/z: 249.0 (M+H)⁺.

Intermediate 40B. Ethyl3-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate: A darkbrown mixture of Intermediate 40A (1.10 g, 4.42 mmol) and2-cyano-3-ethoxy-2-propenoic acid ethyl ester (0.786 g, 4.64 mmol) inxylene (5.90 ml) was warmed to 160° C. After 72 h, the reaction wasstopped and cooled to rt. The reaction was concentrated to give a brownresidue. Next, 30 mL of a solution of 37% HCl/EtOH (1:2) was added togive a suspension. The suspension was warmed to 100° C. At elevatedtemperature a brown solution formed. After 20 min., the reaction wascooled to rt and the solvent was removed to give a brown residue. Theresidue was partitioned between sat. NaHCO₃ and EtOAc and the layerswere separated. The aqueous layer was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated to give a brown liquid weighing 1.3g. Purification by normal phase chromatography gave an off-white solidweighing 0.269 g. Purification by reverse phase chromatography gaveIntermediate 40B (0.080 g, 6%) as a fluffy, white solid. MS(ESI) m/z:284.0 (M+H)⁺ and 286.0 (M+2+H)⁺.

Intermediate 40.3-Amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid: To awhite suspension of Intermediate 40B (0.075 g, 0.264 mmol) in methanol(2.64 mL) was added 1.0 M NaOH (1.058 mL, 1.058 mmol). The suspensionwas warmed to 50° C. After 3 h, the resulting clear, colorless solutionwas cooled to rt. Then, the reaction was concentrated to give a whitesolid. The solid was dissolved in water and acidified to pH 3-4 with 1.0N HCl to give a white suspension. The suspension was extracted withEtOAc (3×). The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated to give Intermediate 40(0.0708 g, 105%) as a white solid. MS(ESI) m/z: 256.0 (M+H)⁺ and 258.0(M+2+H)⁺.

Intermediate 411-(4-Chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid

Intermediate 101A. 2-Bromo-4-chloro-3-fluoropyridine: To a solution of2,2,6,6-tetramethylpiperidine (1.54 mL, 9.12 mmol) in THF (40 mL) wasadded 1.6 M n-BuLi in hexanes (5.23 mL, 8.36 mmol) dropwise at −78° C.The resulting solution was stirred for 0.5 h at 0° C. It was then cooledto −78° C. and 4-chloro-3-fluoropyridine (0.769 mL, 7.60 mmol) in 5 mLTHF was added dropwise over 30 min. The resulting solution was stirredat −78° C. for 30 min. To the solution was added NBS (1.624 g, 9.12mmol) in THF (25 mL) dropwise and the resulting solution was stirred for1 h at −78° C., then at ambient temperature for 12 h. The reactionmixture was then diluted with EtOAc and water. The organic layer waswashed with brine, concentrated and purified on silica gelchromatography to give the desired product (0.541 g, 34%) as orange oil(volatile). ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=5.0 Hz, 1H), 7.35 (t,J=5.1 Hz, 1H).

Intermediate 41B. 4-Chloro-3-fluoro-2-hydrazinylpyridine, 2HCl: Inmicrowave vial was added toluene (3 mL) and purged with N₂ for 5 min.tert-Butyl carbazate (128 mg, 0.950 mmol), Intermediate 101A (200 mg,0.950 mmol), Cs₂CO₃ (310 mg, 0.950 mmol), DPPF (20 mg, 0.036 mmol), andPd₂(dba)₃ (25 mg, 0.027 mmol) were added sequentially into the solution.The sealed tube was heated at 100° C. for 12 h. The reaction was dilutedwith brine, and extracted with EtOAc (2×). The combined organic layerwas concentrated in vacuo, yielding oily residue, which was purified bysilica gel chromatography to provide tert-butyl2-(4-chloro-3-fluoropyridin-2-yl)hydrazinecarboxylate (41 mg, 16%) asorange solid. MS(ESI) m/z: 262.1 (M+H)⁺. To the solid was added EtOH (1mL) and 4 N HCl in dioxane (4 mL) and the reaction mixture was stirredfor 2 h at rt. The mixture was concentrated to dryness to the desiredproduct. MS(ESI) m/z: 162.1 (M+H)⁺.

Intermediate 41.1-(4-Chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylicacid: To a solution of tert-butyl2-((dimethylamino)methylene)-3-oxobutanoate (0.045 g, 0.211 mmol) inacetonitrile (2 mL) was added TEA (0.030 mL, 0.215 mmol) followed byIntermediate 41B (0.038 g, 0.19 mmol). The dark brown solution wasstirred for 1 h at 85° C. The reaction was concentrated, and water (1mL) and CH₂Cl₂ (1 mL) were added. The organic layer was concentrated andpurified by silica gel chromatography to provide tert-butyl1-(4-chloro-3-fluoro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate asbrown oil. MS(ESI) m/z: 312.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.39-8.25(m, 1H), 8.04 (s, 1H), 7.51 (t, J=5.0 Hz, 1H), 2.57 (s, 3H), 1.48 (s,9H). The oil was stirred with 4 N HCl in dioxane (2 mL) for 12 h at rt.The solution was evaporated to dryness followed by coevaporation withtoluene (2×) to give the desired product (12 mg, 22%). MS(ESI) m/z:256.1 (M+H)⁺.

Intermediate 421-(4-Chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid

Intermediate 42A. 4-Chloro-2-hydrazinylpyridine, 2HCl: In microwave vialwas added toluene (4 mL) and purged with N₂ for 5 min. tert-Butylcarbazate (66.6 mg, 0.494 mmol), 2-bromo-4-chloropyridine (95 mg, 0.494mmol), Cs₂CO₃ (161 mg, 0.494 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (4.03mg, 4.94 μmol) were added. The sealed tube was heated at 100° C. for 5h. To the reaction mixture was added water, brine and the mixture wasextracted with EtOAc (2×). The combined organic layer was concentratedand purified by silica gel chromatography to provide tert-butyl2-(4-chloropyridin-2-yl)hydrazinecarboxylate (42 mg, 35%) as red oil.MS(ESI) m/z: 244.2 (M+H)⁺. To the above oil was added 4 N HCl in dioxane(2 mL) and the reaction was stirred at rt for 2 h. The mixture wasconcentrated to dryness to give the desired (36 mg, 34%) as a whitesolid. MS(ESI) m/z: 144.0 (M+H)⁺.

Intermediate 42.1-(4-Chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To asolution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate(0.032 g, 0.148 mmol) in acetonitrile (2 mL) was added TEA (0.021 mL,0.148 mmol) and Intermediate 42A (0.024 g, 0.133 mmol). The dark brownsolution was heated to 85° C. for 1 h. The reaction mixture wasconcentrated, and water (1 mL) and CH₂Cl₂ (1 mL) were added. The organiclayer was concentrated and purified by silica gel chromatography to givetert-butyl 1-(4-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate(12 mg, 27%) as yellow oil. MS(ESI) m/z: 294.2 (M+H)⁺. To the oil wasadded 4 N HCl in dioxane (2 mL). The reaction was stirred at rt for 4 h,and the clear orange solution was evaporated to dryness followed bycoevaporation with toluene (2×) to give the desired product as stickypink solid. MS(ESI) m/z: 238.2 (M+H)⁺.

Intermediate 431-(3-Fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid

Intermediate 43A. 3-Fluoro-2-hydrazinyl-4-methylpyridine: In a microwavevial, a solution of hydrazine monohydrate (0.051 mL, 1.053 mmol),2-bromo-3-fluoro-4-methylpyridine (200 mg, 1.053 mmol), DIEA (0.551 mL,3.16 mmol) in isopropanol (2 mL) was heated at 50° C. overnight.Additional hydrazine monohydrate (0.100 mL) was added and the reactionwas heated at 100° C. for 30 min, then 120° C. for 30 min in a microwavereactor. Additional hydrazine monohydrate (0.100 mL) was added and thereaction was heated at 120° C. overnight. The volatile organics wereremoved in vacuo and the residue was washed with CH₂Cl₂. The resultingsolid was filtered to provide the desired product. MS(ESI) m/z: 142.0(M+H)⁺.

Intermediate 43.1-(3-Fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylicacid: To a solution of tert-butyl2-((dimethylamino)methylene)-3-oxobutanoate (0.123 g, 0.575 mmol) inacetonitrile (2 mL) was added TEA (0.080 mL, 0.575 mmol) andIntermediate 43A (0.073 g, 0.517 mmol). The orange solution was heatedto 85° C. for 1 h. Additional tert-butyl2-((dimethylamino)methylene)-3-oxobutanoate (0.160 mL) and Et₃N (0.080mL) were added into the solution and the reaction was heated at 85° C.for 1 h. The reaction mixture was concentrated and purified by silicagel chromatography to give tert-butyl1-(3-fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate asyellow oil. MS(ESI) m/z: 292.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.26(d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.29 (t, J=4.8 Hz, 1H), 2.54 (s, 3H),2.43 (d, J=1.5 Hz, 3H), 1.58 (s, 9H). To the oil was added 4 N HCl indioxane (2 mL) and the reaction was stirred at rt for 4 h. The clearorange solution was evaporated to dryness followed by coevaporation withtoluene (2×) to give the desired product (15 mg, 11%) as sticky pinksolid. MS(ESI) m/z: 236.1 (M+H)⁺.

Intermediate 441-(3-Fluoro-4-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid

Intermediate 44A. Methyl1-(3-fluoro-4-methylpyridin-2-yl)-1H-imidazole-4-carboxylate: Asuspension of methyl 1H-imidazole-4-carboxylate (83 mg, 0.658 mmol),2-bromo-3-fluoro-4-methylpyridine (200 mg, 1.053 mmol), copper (I)iodide (125 mg, 0.658 mmol) and potassium carbonate (546 mg, 3.95 mmol)in DMSO (2 mL) was heated at 120° for 90 min under microwave conditions.The reaction mixture was quenched with H₂O, and the solid was suspendedin EtOAc and MeOH. The combined organic layer was concentrated in vacuo,yielding oily residue, which was purified by reverse phase HPLC to givethe desired product (5 mg, 3%). MS(ESI) m/z: 236.1 (M+H)⁺.

Intermediate 44.1-(3-Fluoro-4-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid: To asolution of Intermediate 44A (5 mg, 0.021 mmol) in THF (0.6 mL) and H₂O(0.3 mL) was added LiOH (5 mg). The reaction was stirred for 12 h at rt.The THF was removed in vacuo and 1 N HCl aq. solution was added untilthe solution became acidic. The mixture was extracted with EtOAc (2×).The combined organic layer was concentrated to dryness to give thedesired product (4 mg, 3%) as a white solid. MS(ESI) m/z: 222.1 (M+H)⁺.

Intermediate 45 (R)-2-Methylbut-3-enoic acid

Intermediate 45A.(R)-4-Benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one: To thesolution of 2-methylbut-3-enoic acid (5.59 g, 55.9 mmol) andN-methylmorpholine (6.14 ml, 55.9 mmol) in THF (62 mL) at 0° C. wasadded pivaloyl chloride (6.87 ml, 55.9 mmol) dropwise. The reactionmixture was cooled down to −78° C., and stirred for ˜2 h. In a separateflask: To the solution of (R)-4-benzyloxazolidin-2-one (8.25 g, 46.6mmol) in THF (126 mL) at −78° C. was added dropwise N-butyllithium (2.5M in hexane) (20.49 mL, 51.2 mmol). After 35 min, this reaction wastransferred via cannula to the first reaction. The reaction mixture wasstirred at −78° C. for 2 h, then the cold bath was removed, and thereaction was quenched with saturated NH₄Cl. The reaction was dilutedwith water and extracted with EtOAc (3×). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated togive a yellow oil (15 g). Purification by silica gel chromatographyafforded the desired product (6.59 g, 55%) as a colorless oil. MS(ESI)m/z: 282.1 (M+Na)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.36-7.19 (m, 5H),6.03-5.93 (m, 1H), 5.23-5.10 (m, 2H), 4.69-4.63 (m, 1H), 4.51-4.43 (m,1H), 4.23-4.15 (m, 2H), 3.29 (dd, J=13.5, 3.3 Hz, 1H), 2.79 (dd, J=13.5,9.6 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H) ppm. The other diastereomer(R)-4-benzyl-3-((S)-2-methylbut-3-enoyl)oxazolidin-2-one (4.6 g, 38%)also obtained as a white solid. MS(ESI) m/z: 260.1 (M+H)⁺.

Intermediate 45. (R)-2-Methylbut-3-enoic acid: To a clear colorlesssolution of Intermediate 45A (6.05 g, 23.33 mmol) in THF (146 mL) at 0°C. was added dropwise hydrogen peroxide (9.53 mL, 93 mmol) (30% aqueous)followed by 2 N lithium hydroxide (23.33 mL, 46.7 mmol). After 30 min,the reaction was quenched with 25 mL of saturated Na₂SO₃ and 25 mL ofsaturated NaHCO₃. The reaction was then concentrated to remove the THF.The residue was diluted with water and extracted with CHCl₃ (3×). Theaqueous layer was acidified with conc. HCl to pH˜3 and then it wasextracted with EtOAc (3×). The EtOAc layers were combined, washed withbrine, dried over MgSO₄, filtered and concentrated to afford the desiredproduct (2.15 g, 92%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ10.84 (br. s., 1H), 5.94 (ddd, J=17.4, 10.1, 7.4 Hz, 1H), 5.22-5.13 (m,2H), 3.23-3.15 (m, 1H), 1.31 (d, J=7.2 Hz, 3H) ppm.

Intermediate 463-(3-Chloro-2-fluorophenyl)-4-methylisoxazole-5-carboxylic acid

Intermediate 46A. (E)-3-Chloro-2-fluorobenzaldehyde oxime: To thesolution of 3-chloro-2-fluorobenzaldehyde (1.3 g, 8.20 mmol) andhydroxylamine hydrochloride (0.695 g, 10.00 mmol) in EtOH (6.83mL)/water (6.83 mL) was added 1 N NaOH (10.00 mL, 10.00 mmol). Thereaction was stirred at rt for 4 h, then it was acidified to pH 6 with 1N HCl which gave a white suspension. The reaction mixture was filtered,and the solid was rinsed with water, and air-dried to afford the desiredproduct (1.31 g, 92%) as a white solid. MS(ESI) m/z: 174.0 (M+H)⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.36 (s, 1H), 7.74 (s, 1H), 7.66 (ddd, J=7.8,6.3, 1.7 Hz, 1H), 7.42 (ddd, J=8.0, 7.2, 1.7 Hz, 1H), 7.13-7.07 (m, 1H)ppm.

Intermediate 46B. Ethyl3-(3-chloro-2-fluorophenyl)-4-methylisoxazole-5-carboxylate: Ethylbut-2-ynoate (0.725 ml, 6.22 mmol) and Intermediate 46A (0.36 g, 2.074mmol) were dissolved in acetonitrile (10.37 mL). Magtrieve (1.742 g,20.74 mmol) was added and the reaction mixture was stirred in a sealedtube at 80° C. After 2 h, the reaction was cooled to rt and then it wasfiltered through CELITE®, rinsing with EtOAc. The filtrate wasconcentrated and purified by reverse phase HPLC to afford the desiredproduct (0.009 g, 2% yield) as a white solid. MS(ESI) m/z: 284.0 (M+H)⁺.¹H NMR (500 MHz, MeOD) δ 7.70 (ddd, J=8.0, 7.2, 1.7 Hz, 1H), 7.49 (ddd,J=7.8, 6.3, 1.7 Hz, 1H), 7.35 (td, J=7.8, 1.1 Hz, 1H), 4.46 (q, J=7.2Hz, 2H), 2.25 (d, J=1.9 Hz, 3H), 1.42 (t, J=7.2 Hz, 3H) ppm. The otherregioisomer, ethyl3-(3-chloro-2-fluorophenyl)-5-methylisoxazole-4-carboxylate (0.083 g,14%) was also obtained as a colorless oil. MS(ESI) m/z: 284.0 (M+H)⁺.

Intermediate 46.3-(3-Chloro-2-fluorophenyl)-4-methylisoxazole-5-carboxylic acid: To thesolution of Intermediate 46B (0.011 g, 0.039 mmol) in MeOH (1 mL) wasadded 1 N NaOH (0.078 mL, 0.078 mmol). After 18 h, the reaction wasquenched with 1 N HCl (0.1 mL) and then it was concentrated to give thedesired product (10 mg, 100% yield) as a white solid. MS(ESI) m/z: 255.9(M+H)⁺. The material was carried onto the next step without furtherpurification.

Intermediate 475-(3-Chloro-2-fluorophenyl)-4-methylisoxazole-3-carboxylic acid

Intermediate 47A. 1-(3-Chloro-2-fluorophenyl)propan-1-ol: To thesolution of 3-chloro-2-fluorobenzaldehyde (2.8 g, 17.66 mmol) in THF (88mL) at −78° C. was added dropwise ethylmagnesium bromide (1 M in THF)(21.19 mL, 21.19 mmol). After 2 h, the reaction was warmed to 0° C. andit was carefully quenched with saturated NH₄Cl solution. The reactionmixture was diluted with water and extracted with EtOAc (3×). Theorganic layers were combined and washed with water, brine, dried overMgSO₄, filtered and concentrated. Purification by silica gelchromatography yielded the desired product (2.04 g, 61%) as a colorlessoil. MS(ESI) m/z: 211.0 (M+Na)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.37 (td,J=7.0, 1.7 Hz, 1H), 7.33-7.28 (m, 1H), 7.09 (td, J=7.8, 1.1 Hz, 1H),4.99-4.94 (m, 1H), 1.92 (d, J=4.4 Hz, 1H), 1.85-1.77 (m, 2H), 0.95 (t,J=7.4 Hz, 3H) ppm.

Intermediate 47B. 1-(3-Chloro-2-fluorophenyl)propan-1-one: To thesolution of Intermediate 47A (1.9 g, 10.07 mmol) in DCM (40.3 ml) wasadded PDC (11.37 g, 30.2 mmol) and 4 Å MS (2 g) (powdered). The reactionwas stirred at rt for 24 h, then it was filtered through CELITE® washingwith DCM. The filtrate was concentrated. Purification by silica gelchromatography yielded the desired product (1.6 g, 85%) as a colorlessoil. MS(ESI) m/z: 187.0 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.74 (ddd,J=7.9, 6.3, 1.8 Hz, 1H), 7.58-7.53 (m, 1H), 7.17 (td, J=7.8, 0.8 Hz,1H), 3.00 (qd, J=7.2, 3.3 Hz, 2H), 1.21 (td, J=7.2, 0.7 Hz, 3H) ppm.

Intermediate 47C. Ethyl4-(3-chloro-2-fluorophenyl)-3-methyl-2,4-dioxobutanoate: To the solutionof LiHMDS (1 M in THF) (3.19 mL, 3.19 mmol) in ether (12 mL) at −78° C.was added dropwise a solution of Intermediate 47B (0.59 g, 3.16 mmol) inether (2 mL). After 45 min., diethyl oxalate (0.492 mL, 3.60 mmol) wasadded in one portion, and the reaction was warmed to rt. After 18 h, thereaction mixture was filtered, washing with ether. The filtrate wasdiluted with EtOAc, washed with 1 N HCl, brine, dried over Na₂SO₄,filtered and concentrated. Purification by silica gel chromatographyyielded the desired product (0.057 g, 6%) as a yellow oil. MS(ESI) m/z:241.0 (M-OEt)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.80 (ddd, J=8.0, 6.3, 1.7 Hz,1H), 7.65 (ddd, J=7.8, 7.0, 1.9 Hz, 1H), 7.23 (td, J=8.0, 0.8 Hz, 1H),4.91 (q, J=7.2 Hz, 1H), 4.31 (qd, J=7.2, 0.8 Hz, 2H), 1.46 (dd, J=7.2,0.8 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H) ppm.

Intermediate 47D. Ethyl5-(3-chloro-2-fluorophenyl)-4-methylisoxazole-3-carboxylate: The mixtureof Intermediate 47C (0.057 g, 0.199 mmol) and hydroxylaminehydrochloride (0.017 g, 0.239 mmol) in EtOH (1 mL) was heated in asealed tube at 90° C. After 5 h, the reaction was cooled to rt and thenit was concentrated. Purification by reverse phase HPLC afforded thedesired product (0.022 g, 39%) as a white solid. MS(ESI) m/z: 284.0(M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 7.73-7.68 (m, 1H), 7.56 (ddd, J=7.8,6.2, 1.7 Hz, 1H), 7.37 (td, J=8.0, 1.1 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H),2.24 (d, J=2.2 Hz, 3H), 1.42 (t, J=7.2 Hz, 3H) ppm.

Intermediate 47.5-(3-Chloro-2-fluorophenyl)-4-methylisoxazole-3-carboxylic acid: To thesolution of Intermediate 47D (0.009 g, 0.032 mmol) in MeOH (1 mL) wasadded 1 N NaOH (0.063 mL, 0.063 mmol). After 3 h, the reaction wasquenched with 1 N HCl (0.1 mL) and then it was concentrated to give thedesired product (8.1 mg, 100% yield) as a white solid. MS(ESI) m/z:255.9 (M+H)⁺. The material was carried onto the next step withoutfurther purification.

Intermediate 48 (R)-2-Methylbut-3-enoyl chloride

Intermediate 48. (R)-2-Methylbut-3-enoyl chloride: To a cooled (0° C.)solution of (R)-2-methylbut-3-enoic acid (0.450 g, 4.49 mmol) in DCM wasadded dropwise oxalyl chloride (0.393 mL, 4.49 mmol). The reactionmixture was stirred at 0° C. for 30 min and then it was allowed to stirat rt for 80 min. The resulting solution of (R)-2-methylbut-3-enoylchloride was used directly.

Intermediate 492-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitro-phenylamine

To a flame-dried flask, equipped with a reflux condenser, containing2-bromo-5-nitroaniline (10.0 g, 46.1 mmol), bis(neopentylglycolato)diboron (13.01 g, 57.6 mmol), potassium acetate (13.57 g, 138mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (0.941 g, 1.152 mmol) was addedDMSO (132 mL). The resulting dark red-brown suspension was degassed withargon for 30 min and then the reaction was warmed to 80° C. After 4 h,the reaction was stopped and cooled to rt. The reaction was pouredslowly into vigorously stirred ice-cold water (300 mL) to give a brownsuspension. After stirring for 10 min, the suspension was filtered tocollect the solid. The solid was rinsed with water (3×125 mL),air-dried, and then dried under a vacuum to give a brown solid.Purification by normal phase chromatography gave 4.36 g of Intermediate49 as an orange solid. MS(ESI) m/z: 183.1 (M-C₅H₈+H)⁺.

Intermediate 504-Chloro-5-(3-chloro-2-fluorophenyl)isothiazole-3-carboxylic acid

Intermediate 50A. Methyl 4,5-dichloroisothiazole-3-carboxylate: To asolution of 4,5-dichloroisothiazole-3-carboxylic acid (211 mg, 1.07mmol) in toluene (3 mL)) and MeOH (1 mL) was addedtrimethylsilyldiazomethane (2 M in hexane) (0.7 mL, 1.400 mmol) solutiondropwise. The pale yellow solution was stirred at rt for 0.5 h. Thesolution was concentrated under vacuum to give yellow solid, which wassubjected to the following reaction without further purification.MS(ESI) m/z: 212.1 (M+H)⁺.

Intermediate 50B. Methyl4-chloro-5-(3-chloro-2-fluorophenyl)isothiazole-3-carboxylate: To asolution of Intermediate 50A (0.100 g, 0.472 mmol) and Cs₂CO₃ (0.461 g,1.415 mmol) in DME (3.02 mL) and water (0.605 mL) was added methyl4,5-dichloroisothiazole-3-carboxylate (0.100 g, 0.472 mmol). Thesolution was purged with Ar for 0.5 h. To the solution was addedPd(PPh₃)₄ (0.054 g, 0.047 mmol). The reaction mixture was then sealedand heated in microwave for 0.5 h at 100° C. The reaction mixture wasthen diluted with EtOAc and aqueous layer was decanted. The organiclayer was concentrated in vacuo, yielding an oily residue which waspurified by silica gel column chromatography to provide the desiredproduct (53 mg, 37%) as a white solid. MS(ESI) m/z: 360.0 (M+H)⁺.

Intermediate 50.4-Chloro-5-(3-chloro-2-fluorophenyl)isothiazole-3-carboxylic acid: To asolution of Intermediate 50B (53 mg, 0.173 mmol) in THF (2 mL) and water(1 mL) was added lithium hydroxide monohydrate (0.014 mL, 0.519 mmol).The resulting solution was stirred for 2 h at rt. The reaction mixturewas concentrated in vacuo. The aqueous solution was acidified with 1 NHCl (pH=2-3) and extracted with EtOAc (2×). The organic solution wasdried over Na₂SO₄, filtered and concentrated in vacuo to provide thedesired product as a white solid (47 mg, 93%). MS(ESI) m/z: 291.1(M+H)⁺.

Intermediate 51 5-(3-Chloro-2-fluorophenyl)nicotinic acid, HCl

Intermediate 51A. Ethyl 5-(3-chloro-2-fluorophenyl)nicotinate: To asolution of (3-chloro-2-fluorophenyl)boronic acid (148 mg, 0.848 mmol),ethyl 5-bromonicotinate (150 mg, 0.652 mmol), tetrabutylammonium bromide(315 mg, 0.978 mmol) and Cs₂CO₃ (637 mg, 1.956 mmol) in dimethoxyethane(9 mL) and water (1 mL) was added Pd(Ph₃P)₄ (113 mg, 0.098 mmol) and theresulting heterogeneous solution was purged with N₂. It was then sealedand heated at 120° C. for 0.5 h in a microwave reactor. The reactionmixture was diluted with DCM and washed with brine (2×). The organicsolution was dried over Na₂SO₄, filtered and concentrated in vacuo,yielding oily residue which was purified by silica gel columnchromatography to provide the desired product (100 mg, 55%). MS(ESI)m/z: 280.1 (M+H)⁺.

Intermediate 51. 5-(3-Chloro-2-fluorophenyl)nicotinic acid: To asolution of Intermediate 51 A (100 mg, 0.358 mmol) in THF (4 mL) andwater (3 mL) was added lithium hydroxide monohydrate (0.030 mL, 1.073mmol) and the resulting solution was stirred for 2 h at rt. The reactionmixture was concentrated in vacuo. The aqueous solution was acidifiedwith 1 N HCl (pH=2-3). At this point, a white solid was precipitatedfrom the solution. The solid was collected by filtration and dried undervacuum to provide Intermediate 51 (102 mg, 99%) as a white solid.MS(ESI) m/z: 252.1 (M+H)⁺.

Example 1 MethylN-[(14S)-14-[1-(3-chlorophenyl)-3-(2-hydroxyethyl)-1H-pyrazole-4-amido]-16-fluoro-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt

1A.(R,E)-N-((5-Bromo-2-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide:To the solution of 5-bromo-2-fluoronicotinaldehyde (5 g, 24.51 mmol),titanium (IV) ethoxide (15.42 ml, 73.5 mmol) in DCM (49.0 ml) was added(R)-2-methylpropane-2-sulfinamide (3.12 g, 25.7 mmol) and the reactionmixture was stirred at rt. After 48 h, the reaction mixture was pouredinto brine while rapidly stirring to form a suspension. The resultingsuspension was filtered through a plug of CELITE®, and the filter cakewas washed several times with DCM. The filtrate phases were separated,and the organic phase was washed with brine and dried over MgSO₄. Theorganic layers were then concentrated to give 7.6 g crude product whichwas further purified using silica gel chromatography to yield thedesired product (6.97 g, 93%) as an off white solid. MS(ESI) m/z: 330.8(M+Na)⁺.

1B.(R)—N—((S)-1-(5-Bromo-2-fluoropyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide:To a saturated aqueous solution of sodium bromide (420 g, 4084 mmol)(app. 420 g in 450 ml H₂O) was added 1A (6.97 g, 22.69 mmol) and indium(10.42 g, 91 mmol). To this mixture was then added 3-bromoprop-1-ene(7.85 ml, 91 mmol) dropwise, and the resulting cloudy white suspensionwas allowed to stir at rt for 10 h. The reaction was then quenched withsaturated aqueous NaHCO₃ solution followed by extraction with EtOAc. Theorganic layer was dried over anhydrous MgSO₄ and concentrated to yieldthe crude product. The crude product was then purified using silica gelchromatography to give the desired product (8.8 g, 98%) as an off whitesolid. MS(ESI) m/z: 350.8 (M+H)⁺.

1C. (S)-1-(5-Bromo-2-fluoropyridin-3-yl)but-3-en-1-amine, 2 HCl: To asolution of 1B (8.8 g, 25.2 mmol) in MeOH (100 mL) was added HCl (31.5mL, 126 mmol) (4 M in dioxane). The reaction mixture was stirred at rtfor 1 h and then concentrated to near dryness. Et₂O was added to give ayellow suspension which was then filtered and the filtered solid wasfurther washed with Et₂O. The filtrate was concentrated and re-filteredwith Et₂O. The collected solid was then dried on the vacuum pump to give1C (6.45 g, 80%) as a white solid. MS(ESI) m/z: 246.9 (M+H)⁺.

1D. (S)-tert-Butyl(1-(5-bromo-2-fluoropyridin-3-yl)but-3-en-1-yl)carbamate: To a solutionof 1C (6.55 g, 20.60 mmol) in DCM (68.7 ml) at 0° C. was added TEA(11.48 ml, 82 mmol) and Boc₂O (4.50 g, 20.60 mmol). The reaction mixturewas stirred at 0° C. for 2 h, and then allowed to warm to rt. Afterstirring for 2 h, the reaction mixture was diluted with DCM and washedwith saturated NaHCO₃ solution. The aqueous layer was re-extracted withDCM (2×). The combined organic layers were then washed with brine, driedover MgSO₄ to yield the crude product. The crude product was thenpurified using silica gel chromatography to yield the desired product(6.64 g, 87%) as a white solid. MS(ESI) m/z: 368.9 (M+Na)⁺.

1E. (S)-tert-Butyl(1-(5-(2-amino-4-nitrophenyl)-2-fluoropyridin-3-yl)but-3-en-1-yl)carbamate:To a RBF was added 1D (4.5 g, 13.04 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitroaniline (6.52 g, 26.1mmol), PdCl₂(dppf)-DCM adduct (1.065 g, 1.304 mmol), and potassiumphosphate, tribasic (5.53 g, 26.1 mmol). The RBF was equipped with areflux condenser and the apparatus was vacuumed and back-filled withargon. Degassed DMSO (65.2 mL) was added followed by degassed H₂O (1.174mL, 65.2 mmol). The dark red reaction mixture was warmed to 90° C. for 1h, and then allowed to cool to rt. The reaction mixture was thenpartitioned between EtOAc and brine, and the layers were separated. Theaqueous layer was re-extracted with EtOAc. The combined organic layerswere dried over MgSO₄, filtered and concentrated to give the crudeproduct as thick black oil which was subjected to silica gelchromatography to yield the desired product (5.90 g, 100%) as yellowfoam. MS(ESI) m/z: 403.0 (M+H)⁺.

1F. Methyl(3-amino-4-(5-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-6-fluoropyridin-3-yl)phenyl)carbamate:To a clear, orange solution of 1E (4.4 g, 9.95 mmol) in MeOH (100 mL)was added sequentially zinc (6.51 g, 99 mmol) and ammonium chloride(5.32 g, 99 mmol). The resulting yellow-orange suspension turned clearafter a few minutes and was stirred at rt. After 2 h, the reactionmixture was filtered off to remove solid and concentrated to give aresidue. The residue was diluted with EtOAc and washed with saturatedNaHCO₃ solution. The organic layer was then dried over MgSO₄ andpurified by silica gel chromatography to yield the desired bis amineproduct as peach colored foam. To a −78° C. clear, orange solution ofthe above bis amine product (5.08 g, 13.64 mmol) and pyridine (1.103 ml,13.64 mmol) in DCM (136 mL) was added dropwise methyl chlorocarbonate(0.949 ml, 12.28 mmol) and the reaction mixture was stirred at −78° C.for 1.5 h. The reaction was then quenched with saturated NH₄Cl solutionand allowed to slowly warm to rt. The reaction mixture was diluted withDCM and the aqueous layer was re-extracted with DCM. The combinedorganic layers were washed with saturated NaHCO₃ solution followed bybrine. The organic layer was then dried over MgSO₄, filtered andconcentrated to give the crude product as peach-colored foam which wasthen purified using silica gel chromatography. COSY and NOE analysisconfirmed the site of addition. The desired product (4.77 g, 81%) wasisolated as beige foam. MS(ESI) m/z: 431.1 (M+H)⁺.

1G. Methyl(4-(5-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-6-fluoropyridin-3-yl)-3-((2-methylbut-3-enoyl)amino)phenyl)carbamate:To a solution of 2-methylbut-3-enoic acid (0.216 mL, 2.091 mmol) and 1F(0.900 g, 2.091 mmol) in EtOAc (59.7 mL) was added DIEA (1.095 mL, 6.27mmol) and the reaction was allowed to cool to −10° C. under argon. Tothis mixture was then added T3P (2.464 mL, 4.18 mmol) and the reactionwas allowed to stir for 5 min at the same temperature and then allowedto warm to 0° C. followed by to rt slowly while stirring under argon atrt. After overnight stirring, the reaction mixture was concentrated andpurified by silica gel chromatography to give 1G (887 mg, 83%) as awhite solid. MS(ESI) m/z: 513.1 (M+H)⁺.

1H. tert-ButylN-[(11E)-16-fluoro-9-hydroxy-5-[(methoxycarbonyl)amino]-10-methyl-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadec-11-en-14-yl]carbamate:A clear, colorless solution of 11G (887 mg, 1.730 mmol) in DCE (100 mL)was degassed with argon, then split into 5 microwave vials. To the abovemixture was then added Grubbs II (588 mg, 0.692 mmol) (118 mg to eachvial) and heated each vial in the microwave at 120° C. for 25 min. Thereaction mixture was then combined and washed with saturated NaHCO₃followed by brine. The organic layer was then dried over MgSO₄, filteredand concentrated to give the crude product which was purified by silicagel chromatography. Desired fractions were collected and concentrated togive 1H (568 mg, 68%) as a brown solid. MS(ESI) m/z: 485.1 (M+H)⁺.

1I. tert-ButylN-[(14S)-16-fluoro-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl]carbamate:To a solution of 1H (0.568 g, 1.172 mmol) in MeOH (39.1 mL) was addedplatinum (IV) oxide (0.027 g, 0.117 mmol). The reaction mixture was thencharged with H₂ gas using a H₂ balloon and vacuumed with H₂ severaltimes. The reaction was then stirred at rt under H₂ for 40 h. Afterstirring for 40 h, the reaction mixture was filtered through a pad ofCELITE® and the filtrate was concentrated to yield the crude product.The crude product was then purified by silica gel chromatography toyield the Diastereomer A (Ha) (178 mg, 25%) and Diastereomer-B (95 mg,14%, 1Ib) as white solids. Diastereomer A—MS(ESI) m/z: 487.1 (M+H)⁺.

1J. MethylN-[(14S)-14-amino-16-fluoro-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate:A solution of hydrogen chloride in dioxane (5932 μL, 23.73 mmol) wasadded to 1Ia (95 mg, 0.158 mmol) and the reaction mixture was stirred atrt. After 1 h of stirring, the reaction mixture was concentrated to givethe desired product (73 mg, 100%). MS(ESI) m/z: 387.1 (M+H)⁺.

Example 1. MethylN-[(14S)-14-[1-(3-chlorophenyl)-3-(2-hydroxyethyl)-1H-pyrazole-4-amido]-16-fluoro-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt: A mixture of Intermediate 9 (0.030 g, 0.112 mmol), 1J (0.043g, 0.112 mmol), DIEA (0.60 mL, 0.334 mmol) and T3P (0.115 mmol) in DMF(2 mL) was stirred at rt overnight. The reaction mixture wasconcentrated and purified directly by reverse phase HPLC to isolate thedesired product as a homochiral compound. ¹H NMR (400 MHz, MeOD) δ 8.59(s, 1H), 8.01-7.99 (m, 1H), 7.96-7.95 (dd, J=8.3 & 1.3 Hz, 1H),7.67-7.49 (m, 3H), 7.48-7.39 (m, 1H), 7.38-6.37 (m, 2H), 7.26-7.24 (m,1H), 5.17-4.93 (m, 1H), 3.82-3.57 (t, J=6.3 Hz, 2H), 3.02 (t, J=6.3 Hz,2H), 2.23-2.00 (m, 1H), 1.96 (m, 1H), 1.82 (m, 1H), 1.51-1.49 (m, 1H),1.36 (m, 2H), 1.12-1.10 (d, 2H), 0.92 (m, 1H) ppm. MS(ESI) m/z: 635.1(M+H)⁺. Analytical HPLC RT=6.44 min (Method B).

Example 2 MethylN-[(10R,14S)-14-[1-(3-chlorophenyl)pyrrolidine-3-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,2TFA

2A.(S,E)-N-((4-Chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide:Liu, G. et al., J. Org. Chem., 64:1278 (1999). To a solution ofS-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in dichloromethane (14.13mL) was added sequentially copper(II) sulfate (2.481 g, 15.54 mmol) and4-chloropicolinaldehyde [1.0 g, 7.06 mmol, prepared according to amodified described by Negi (Synthesis, 991 (1996))]. The whitesuspension was stirred at rt. After 3 h, the brown suspension wasfiltered through CELITE®, eluting with DCM, to give a clear brownfiltrate. Concentration gave a brown oil weighing 1.85 g. Purificationby normal phase chromatography gave 1.31 g of 2A as a clear, yellow oil.MS(ESI) m/z: 245.0 (M+H)⁺.

2B.(S)—N—((S)-1-(4-Chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide:To a cooled solution (−78° C.) of 2A (10 g, 40.9 mmol) in THF (204 mL)was added dropwise allyl magnesium bromide (44.9 mL, 44.9 mmol, 1M inEt₂O). The reaction mixture was stirred at −78° C. After 2 h, thereaction mixture was quenched with the addition of saturated NH₄Cl (25mL) and then the reaction mixture was allowed to warm to rt. Thereaction mixture was then diluted with EtOAc and water and the layerswere separated. The aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. Purification by normal phase chromatography gave 2B (9.23g, 79%) as a clear, orange oil. ¹H NMR indicated a 4.7:1 mixture ofdiastereomers whereby the major diastereomer corresponds to the titlecompound. MS(ESI) m/z: 287.1 (M+H)⁺.

2C.(S)—N—((S)-1-(4-(2-Amino-4-nitrophenyl)pyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide,Diastereomer A and 2D.(S)—N—((R)-1-(4-(2-amino-4-nitrophenyl)pyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide,Diastereomer B: To a RBF was added 2B (9.23 g, 32.2 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitroaniline (16.09 g, 64.4mmol), potassium phosphate, tribasic (13.66 g, 64.4 mmol), DMSO (161mL), and water (2.90 mL, 161 mmol). The RBF was equipped with a refluxcondenser and then the apparatus was purged with argon for 30 minutes.Next, Pd(dppf)Cl₂—CH₂Cl₂ adduct (2.63 g, 3.22 mmol) was added and thereaction mixture was warmed to 90° C. After 4 h, the reaction was cooledto rt and then it was poured into water (1000 mL) to give a suspension.The solid was collected by filtration and then it was dissolved inEtOAc. The filtrate was extracted with EtOAc (1×). The organic layerswere combined and washed with brine, dried over sodium sulfate,filtered, and concentrated. Purification by normal phase chromatographygave 2C (3.9 g) as an orange foam. An additional 3.84 g of material wasobtained as a mixture of diastereomers 2C and 2D. The diastereomers wereseparated by chiral SFC prep HPLC (CHIRALCEL® OD-H; 20% methanol/80%carbon dioxide) which gave 2C (2.0 g) as an orange foam and 2D (0.90 g)as an orange foam. The total amount of 2C isolated was (5.9 g, 47%) asan orange foam. MS(ESI) m/z: 389.2 (M+H)⁺.

2E.(S)—N—((S)-1-(4-(2,4-Diaminophenyl)pyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide:To a clear, orange solution of 2C (2 g, 5.15 mmol) in methanol (51.5 mL)was added sequentially zinc (3.37 g, 51.5 mmol) and ammonium chloride(2.75 g, 51.5 mmol). The resulting suspension was stirred vigorously.After 3 h, the reaction was stopped and it was filtered through a 0.45micron GMF eluting with methanol to give a yellow filtrate. The filtratewas concentrated, then the residue was partitioned between EtOAc andwater, and the layers were separated. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with saturatedsodium bicarbonate, brine, dried over sodium sulfate, filtered, andconcentrated to give 2E (1.86 g, 101%) as a yellow foam. This materialwas used in the next step without further purification. MS(ESI) m/z:359.1 (M+H)⁺.

2F. Methyl3-amino-4-(2-((S)-1-((S)-1,1-dimethylethylsulfinamido)but-3-enyl)pyridin-4-yl)phenylcarbamate:To a cooled (−78° C.) clear, yellow solution of 2E (1.86 g, 5.19 mmol)and pyridine (0.420 mL, 5.19 mmol) in DCM (52 mL) was added dropwisemethyl chlorocarbonate (0.361 mL, 4.67 mmol). The reaction mixture wasstirred at −78° C. After 2 h, the reaction was quenched with saturatedNH₄Cl and the reaction was allowed to warm to rt. The reaction mixturewas then diluted with DCM and water and the layers were separated. Theaqueous layer was extracted with DCM. The combined organic layers werewashed with saturated NaHCO₃, brine, dried over sodium sulfate, filteredand concentrated to give 2F (2.3 g, 106%) as a yellow foam. Thismaterial was used in the next step without further purification. MS(ESI)m/z: 417.1 (M+H)⁺.

2G. (S)-Methyl3-amino-4-(2-(1-aminobut-3-enyl)pyridin-4-yl)phenylcarbamate, 3 HCl: Toa clear, yellow solution of 2F (2.3 g, 5.52 mmol) in MeOH (55.2 mL) wasadded 4 M HCl in dioxane (13.80 mL, 55.2 mmol). The reaction mixture wasstirred at rt. After 2 h, the reaction was concentrated to give a yellowresidue. The residue was suspended in DCM and then it was concentrated.This was repeated one more time to give 2G (2.329 g, 100%) as a yellowsolid. This material was used in the next step without furtherpurification. MS(ESI) m/z: 313.1 (M+H)⁺.

2H. MethylN-(3-amino-4-{2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]pyridin-4-yl}phenyl)carbamate:To a yellow suspension of 2G (2.328 g, 5.52 mmol) in DCM (18.40 mL) wasadded Boc₂O (1.282 mL, 5.52 mmol) followed by TEA (3.08 mL, 22.08 mmol).The resulting orange-brown solution was stirred at rt. After 3 h, thereaction was diluted with DCM and then washed with saturated NaHCO₃,brine, dried over MgSO₄, filtered, and concentrated. Purification bynormal phase chromatography gave 2H (1.91 g, 84%) as an off-white solid.MS(ESI) m/z: 413.0 (M+H)⁺.

2I. MethylN-(4-{2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]pyridin-4-yl}-3-(2-methylbut-3-enamido)phenyl)carbamate(Diastereomers): To a cooled solution (−10° C.) of 2-methylbut-3-enoicacid (0.456 mL, 4.41 mmol) and 2H (1.82 g, 4.41 mmol) in EtOAc (126 mL)and DIEA (2.312 mL, 13.24 mmol) was added dropwise a solution of1-propanephosphonic acid cyclic anhydride in EtOAc (5.20 mL, 8.82 mmol).After 5 min, the reaction was allowed to warm to 0° C. After 7 h, thereaction was stopped and concentrated. Purification by normal phasechromatography gave 21 (1.57 g, 72%) as a mixture of diastereomers andas a yellow solid. MS(ESI) m/z: 495.1 (M+H)⁺.

2J.((E)-(10R,14S)-5-Methoxycarbonylamino-10-methyl-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl)-carbamicacid tert-butyl ester, Diastereomer A and 2K.((E)-(10S,14S)-5-Methoxycarbonylamino-10-methyl-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl)-carbamicacid tert-butyl ester, Diastereomer B: To a RBF was added 21 (1.57 g,3.17 mmol), pTsOH (0.664 g, 3.49 mmol), and DCM (794 mL). The flask wasthen equipped with a reflux condenser and the clear yellow solution wasdegassed with argon for 30 min. The reaction mixture was then warmed to40° C. for 1 h. Then a solution of Grubbs II (0.269 g, 0.317 mmol) inDCM (2 mL) was added dropwise to the reaction mixture. The reactionmixture was then stirred at 40° C. After 6 h, the reaction was cooled tort. The reaction was washed with saturated sodium carbonate, brine,dried over magnesium sulfate, filtered, and concentrated to give thecrude product as a dark brown solid. Purification by normal phasechromatography gave 2J, Diastereomer A (0.374 g, 25%) as a brown solidand a mixture of 2J, Diastereomer A and 2K, Diastereomer B (0.44 g, 30%)as a brown solid. MS(ESI) m/z: 466.9 (M+H)⁺.

2L. MethylN-[(10R,14S)-14-{[(tert-butoxy)carbonyl]amino}-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate:A 500-mL hydrogenation flask was charged with 10% palladium on carbon(0.372 g, 0.349 mmol). The flask was purged with argon and then degassedmethanol (72 mL) was added slowly to the flask. Next, a clear, lightbrown solution 2J (1.63 g, 3.49 mmol) in methanol (5 mL) was added. Theflask was pressurized to 50 psi of hydrogen and the reaction was stirredovernight. After 20 h, the reaction was stopped, diluted with methanol(100 mL) and then the reaction was filtered through CELITE®, rinsingwith methanol to give a clear, light brown filtrate. The filtrate wasconcentrated to give an off-white solid weighing 1.37 g. The off-whitesolid was suspended in methanol (10 mL) and sonicated. The solid wascollected by filtration, rinsed with methanol (8 mL), air-dried, anddried under vacuum to give 2L (1.13 g, 69.0%) as a white solid. MS(ESI)m/z: 469.1 (M+H)⁺.

2M. MethylN-[(10R,14S)-14-amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,2TFA salt: To a white suspension of 2L (0.45 g, 0.960 mmol) in DCM (5mL) was added TFA (3 mL, 38.9 mmol). The resulting clear solution wasstirred at rt. After 1 h, the reaction was concentrated to give a solid.Lyophilization gave 2M (0.52 g, 91%) as a yellow solid. MS(ESI) m/z:369.0 (M+H)⁺.

2M (Alternative, 2HCl): To a flask containing 2L (0.880 g, 1.878 mmol)was added 4.0 M HCl in dioxane (21.13 ml, 85 mmol). The resultingsuspension was sonicated to give a clear, yellow solution. After 5 to 10min, a precipitate formed. After 1 h, the reaction was stopped and theprecipitate was collected by filtration. The solid was rinsed withdioxane and air-dried to give a hygroscopic, yellow solid. The solid wasdissolved in methanol, concentrated, and lyophilized to give 2M(Alternative, 2HCl) (0.7171 g, 87%) as a yellow solid. MS(ESI) m/z:369.3 (M+H)⁺.

Example 2. MethylN-[(10R,14S)-14-[1-(3-chlorophenyl)pyrrolidine-3-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,2TFA: A solution of 2M (0.02 g, 0.034 mmol), Intermediate 11 (0.011 g,0.050 mmol), EDC (0.013 g, 0.067 mmol), HOBT (10.27 mg, 0.067 mmol) andTEA (0.023 mL, 0.168 mmol) in DMF (1 mL) was stirred at 50° C. After 2h, the reaction was cooled to rt and then concentrated. Purification byreverse phase chromatography gave Example 2 (0.012 g, 44%) as a mixtureof diastereomers and as a yellow solid. ¹H NMR (500 MHz, CD₃OD) δ8.80-8.72 (m, 1H), 8.20 (s, 1H), 7.99-7.91 (m, 1H), 7.68-7.48 (m, 3H),7.15-7.07 (m, 1H), 6.65-6.43 (m, 3H), 5.11 (dd, J=10.6, 5.9 Hz, 1H),3.79 (s, 3H), 3.59-3.47 (m, 1H), 3.43-3.26 (m, 4H), 2.82-2.73 (m, 1H),2.37-2.09 (m, 3H), 1.99-1.84 (m, 2H), 1.69-1.47 (m, 2H), 0.97 (d, J=6.9Hz, 3H), 0.55-0.41 (m, 1H) ppm. MS(ESI) m/z: 576.3 (M+H)⁺. AnalyticalHPLC RT=6.70 min.

The preferred sequence for the preparation of compound 2J is describedbelow:

2B (Alternative).(S)—N—((S)-1-(4-Chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide:To a cooled (0-5° C.) mixture of indium(III) chloride (13.56 g, 61.3mmol) in tetrahydrofuran (170 mL) was added dropwise over 30 min.Allylmagnesium bromide (1 M in diethylether) (62 mL, 61.3 mmol). Thereaction was allowed to warm to rt. After 1 h at rt, a solution of 2A(10 g, 40.9 mmol) in ethanol (170 mL) was added. After 2-3 h, thereaction was concentrated under vacuum at 50-55° C. The crude materialwas partitioned between ethyl acetate (200 mL) and water (50 mL) and thelayers were separated. The aqueous layer was extracted with ethylacetate (2×50 mL). The organic layers were combined and washed withbrine (100 mL), dried over sodium sulfate, filtered and concentrated togive 2B (Alternative) (13.5 g, 106%) as a yellow oil. MS(ESI) m/z: 287.2(M+H)⁺. This material was used in the next step without furtherpurification.

2N. (S)-tert-Butyl 1-(4-Chloropyridin-2-yl)but-3-enylcarbamate: Compound2B (Alternative) was converted to 2N in two steps by removal of thechiral auxiliary according to the procedure in step 2G andBoc-protection according to the procedure in step 2H. MS(ESI) 227.3(M-C₄H₈+H)⁺ and 305.4 (M+Na)⁺.

2O. (S)-tert-Butyl1-(4-(2-amino-4-nitrophenyl)pyridin-2-yl)but-3-enylcarbamate: Compound2O was prepared by following the procedure described in step 2C, byreplacing 2B with 2N. MS(ESI) 385.1 (M+H)⁺.

2P. (S)-tert-Butyl1-(4-(2,4-diaminophenyl)pyridin-2-yl)but-3-enylcarbamate: To a clear,orange solution of 2O (2.9 g, 7.54 mmol) in methanol (75 mL) was addedsequentially zinc dust (4.93 g, 75 mmol) and ammonium chloride (4.04 g,75 mmol). The resulting suspension was stirred vigorously for 4 h. Thereaction was stopped and filtered through a 0.45 micron GMF eluting withmethanol to give a clear, yellow filtrate. Concentration of the filtrategave a yellow-black residue. The residue was partitioned between EtOAcand 0.25 M HCl (50 mL) and the layers were separated. The organic layerwas extracted with 0.25 M HCl (50 mL). The combined aqueous layers werebasified with 1.5 M K₂HPO₄ and then extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give 2P (2.63 g, 98%) as a brown foam.MS(ESI) m/z: 355.2 (M+H)⁺.

2Q.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-phenyl}-carbamicacid methyl ester: To a cooled (−78° C.) clear, brown solution of 2P(2.63 g, 7.42 mmol) and pyridine (0.600 ml, 7.42 mmol) indichloromethane (74.2 ml) was added dropwise over 30 min methylchloroformate (0.516 ml, 6.68 mmol). The reaction was stirred at −78° C.After 1.5 h, the reaction was quenched with sat. NH₄Cl and allowed towarm to rt. The reaction was diluted with DCM and water and the layerswere separated. The aqueous layer was extracted with DCM. The combinedorganic layers were washed with saturated NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. The residue dissolved in DCM (˜10 mL)and then hexane (˜300 mL) was added to give a brown suspension withbrown gummy sticky substance at the bottom. The mixture was sonicated togive a mostly clear solution with the brown substance at the bottom. Thesolution decanted and the bottom substance rinsed with hexane, dried togive 2Q (2.7 g, 88%) as a slightly brown foam. MS(ESI) m/z: 413.2(M+H)⁺.

2I (Alternative). MethylN-(4-{2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]pyridin-4-yl}-3-[(2R)-2-methylbut-3-enamido]phenyl)carbamate:Intermediate 45 (1.201 g, 12.00 mmol), 2Q (3.3 g, 8.00 mmol), pyridine(1.937 ml, 24.00 mmol) in EtOAc (40.0 mL) was cooled down to −10° C.under Ar, T3P (50 wt % in EtOAc) (9.52 mL, 16.00 mmol) was addeddropwise and stirred at −10° C., then gradually warmed up to rt overnight. The reaction mixture was washed with saturated NaHCO₃ twice. Thecombined aqueous layer was extracted with EtOAc. The combined EtOAcphase washed with brine, dried over MgSO₄, filtered, concentrated. Thecrude product was then purified using silica gel chromatography to givethe desired the desired product (4.06 g, 97%) as a white solid. ¹H NMR(500 MHz, MeOD) δ 8.46 (d, J=5.0 Hz, 1H), 7.64 (s, 1H), 7.47 (dd, J=8.4,2.1 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.25 (m, 1H),5.87-5.73 (m, 2H), 5.16-5.02 (m, 4H), 4.79-4.71 (m, 1H), 3.75 (s, 3H),3.14-3.05 (m, 1H), 2.64-2.55 (m, 1H), 2.52-2.43 (m, 1H), 1.42 (s, 9H),1.16 (d, J=6.9 Hz, 3H). MS(ESI) m/z: 495.1 (M+H)⁺.

2J (Alternative). MethylN-[(10R,11E,14S)-14-{[(tert-butoxy)carbonyl]amino}-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl]carbamate:To a RBF was added 21 (Alternative) (0.5 g, 1.011 mmol), pTsOHmonohydrate (0.212 g, 1.112 mmol), and dichloromethane (84 ml). Theflask was equipped with a reflux condenser and the clear yellow solutionwas degassed with argon for 30 min. The reaction was then warmed toreflux for 1 h. Then a solution of Grubbs II (0.172 g, 0.202 mmol) inDCM (2 mL) was added dropwise to the reaction mixture. After 4 h atreflux, the reaction was cooled to rt, washed with saturated Na₂CO₃,brine, dried over MgSO₄, filtered, and concentrated to give brown solid.The crude product was then purified using silica gel chromatography togive the desired product (0.336 g, 71%) as a yellow solid. ¹H NMR (500MHz, MeOD) δ 8.52 (d, J=5.2 Hz, 1H), 7.54 (d, J=1.4 Hz, 1H), 7.48-7.43(m, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.24 (dd, J=5.1, 1.5 Hz, 1H), 6.89 (s,1H), 5.75-5.65 (m, 1H), 4.60 (dd, J=11.3, 3.6 Hz, 1H), 4.39 (dd, J=15.1,9.6 Hz, 1H), 3.75 (s, 3H), 3.14-3.06 (m, 1H), 2.75-2.68 (m, 1H),2.04-1.94 (m, 1H), 1.44 (s, 9H), 1.30 (br. s., 1H), 1.04 (d, J=6.6 Hz,3H). MS(ESI) m/z: 467.2 (M+H)⁺.

The following Examples in Table 2 were made by using the same procedureas shown in Example 2. The acids used in the final step are as indicatedin the below table in the Intermediate section. Various couplingreagents could be used other than the one described in Example 2 such asBOP, PyBop, EDC/HOBt or HATU. If needed, the coupled products aresubjected to TFA deprotection condition to remove the tert-Butylprotecting group.

TABLE 2 RT, min Example # Stereochemistry R M + H Method  3 Homochiral

592.0 7.47 A  4 Homochiral

591.1 6.93 A  5 Homochiral

588.0 6.32 A  6 Homochiral

606.4 4.94 D  7 Homochiral

573.0 7.05 A  8 Homochiral

590.3 5.69 A  9 Homochiral

573.4 5.64 A 10 Homochiral

591.4 5.72 A 11 Diastereomer

546.4 2.77 D 12 Homochiral

622.3 5.50 A 13 Homochiral

607.3 6.00 A 14 Homochiral

606.3 4.79 D 15 Homochiral

626.0 5.72 A 16 Homochiral

622.1 5.64 A 17 Homochiral

587.3 5.18 D 18 Homochiral

553.4 4.82 D 19 Homochiral

607.4 6.16 A 20 Homochiral

573.3 5.22 D *Subjected to TFA deprotection

Example 21 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

21A. Methyl(3-(but-3-enoylamino)-4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)phenyl)carbamate:To a solution of but-3-enoic acid (0.412 mL, 4.85 mmol) in EtOAc (100mL) was added DIEA (2.54 mL, 14.55 mmol) and 2G (2 g, 4.85 mmol) and thereaction mixture was allowed to cooled to −78° C. under argon. To thismixture was then added T3P (5.71 mL, 9.70 mmol) and the reaction wasallowed to stir for 15 min at the same temperature and the reactiontemperature was gradually warmed to rt and stirred at rt for overnight.After stirring for overnight at rt, the reaction mixture wasconcentrated to yield dark brown oil which was purified using silica gelchromatography to yield the desired product (1.88 g, 81%) as a whitesolid. MS(ESI) m/z: 481.2 (M+H)⁺.

21B. tert-Butyl methyl((4E,7S)-2-oxo-2,3,6,7-tetrahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-7,15-diyl)biscarbamate:To a RBF was added 21A (1.57 g, 3.27 mmol), pTsOH (0.684 g, 3.59 mmol)and DCM (817 mL). The flask was then equipped with a reflux condenserand the clear yellow solution was degassed with argon for 70 min. Thereaction was then warmed to 40° C. for 1 h. In a separate RBF was addedGrubbs II (1.109 g, 1.307 mmol) and the flask was purged with argon forseveral minutes. Degassed DCM (2 mL) was added to give a clear, burgundysolution. The solution was then added dropwise over 15 min via a syringeto the above reaction. The reaction mixture was stirred at 40-45° C.After stirring for 3 h, the reaction was gradually allowed to cool to rtand stirred at rt overnight. The reaction mixture was then washed withsaturated Na₂CO₃ solution followed by brine. The organic layers werethen dried over MgSO₄, filtered, and concentrated to give dark brownoil. The crude product was purified using silica gel chromatography togive the desired product (395 mg, 26%) as light brown gray solid.MS(ESI) m/z: 453.1 (M+H)⁺.

21C. tert-Butyl methyl((7S)-2-oxo-2,3,4,5,6,7-hexahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-7,15-diyl)biscarbamate:A mixture of 21B (395 mg, 0.873 mmol) and palladium(II) carbon (93 mg,0.087 mmol) in MeOH (5 mL) was stirred under a hydrogen atmosphere(50-55 psi). After stirring for 8 h, the reaction mixture was filteredthrough microfilter to yield the desired product (350 mg, 88%) as redbrown solid. MS(ESI) m/z: 455.2 (M+H)⁺.

21D. Methyl((7S)-7-amino-2-oxo-2,3,4,5,6,7-hexahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecin-15-yl)carbamate:A mixture of 21C (20 mg, 0.044 mmol) and HCl (550 μL, 2.200 mmol) (4 Nin dioxane) was stirred at rt. After stirring for 2 h, the reactionmixture was concentrated to yield a tan yellow powder as the desiredproduct (18 mg, 99%). MS(ESI) m/z: 355.2 (M+H)⁺.

Example 21. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: A mixture of Intermediate 2 (5.57 mg, 0.023 mmol), HOBT (6.45mg, 0.042 mmol), EDC (8.07 mg, 0.042 mmol) and DIEA (0.037 mL, 0.211mmol) in DMF (0.2 mL) was stirred at rt for 15 min. To this mixture wasthen added 21D (9 mg, 0.021 mmol) and stirred at rt for overnight. Thereaction mixture was concentrated and purified by reverse phase HPLC toisolate the desired product (7.2 mg, 48%) as an off white solid. ¹H NMR(500 MHz, CD₃CN) δ 8.82 (d, J=5.78 Hz, 1H), 8.55 (d, J=6.05 Hz, 1H),8.49 (d, J=2.20 Hz, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 8.05 (d, J=J=16,2H), 7.98 (s, 1H), 7.68 (t, J=1.38 Hz, 1H), 7.64 (dd, J=1.65, 6.05 Hz,1H), 7.43 (m, 2H), 7.37 (m, 2H), 7.22 (dt, J=1.51, 8.18 Hz, 1H), 5.31(m, 1H), 3.63 (s, 3H), 2.40 (m, 2H), 2.00 (m, 2H), 1.71 (m, 2H), 1.55(m, 1H), 1.38 (dd, J=3.85, 11.00 Hz, 1H), 0.43 (m, 1H) ppm. MS(ESI) m/z:577.2 (M+H)⁺. Analytical HPLC (Method E) RT=5.79 min.

Example 22 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

22A. (S)-tert-Butyl 1-(dimethoxyphosphoryl)-2-oxohex-5-en-3-ylcarbamate:To a solution of dimethyl methylphosphonate (15.85 ml, 148 mmol) in THF(99 mL) at −78° C. was added n-butyllithium (93 mL, 148 mmol) dropwise.After completion of addition, the reaction was stirred at the sametemperature for 30 min and then a solution of (S)-methyl2-(tert-butoxycarbonylamino)pent-4-enoate (6.8 g, 29.7 mmol) in THF (15mL) was added dropwise. The reaction mixture was then stirred foranother 40 min at −78° C. The reaction was then quenched by adding H₂Oand diluted with EtOAc. The organic layer was washed with 1 M HCl,saturated NaHCO₃ solution and brine. The organic phase was dried overMgSO₄, filtered and concentrated to give clear oil. The crude productwas then purified by silica gel chromatography to give the desiredproduct (9.3 g, 98%) as colorless oil. MS(ESI) m/z: 599.0 (M+Na)⁺.

22B. Methyl 4-iodo-3-nitrophenylcarbamate: To a cooled (0° C.), yellowsuspension of 4-iodo-3-nitroaniline (1.320 g, 5 mmol) in DCM (50.0 mL)and pyridine (0.445 mL, 5.50 mmol) was added dropwise methylchloroformate (0.407 mL, 5.25 mmol) and stirred for 3 h. The reactionwas then diluted with DCM, washed with brine, dried over MgSO₄, filteredand concentrated. The crude product was then dissolved in minimal DCM(˜20 mL) and then hexane (200 mL) was added to give a yellow suspension.The yellow suspension was then filtered and the filtered solid wasrinsed with hexane and air-dried to obtain a yellow solid as the desiredproduct (1.51 g, 94%). MS(ESI) m/z: 322.9 (M+H)⁺.

22C. Methyl 4-acetyl-3-nitrophenylcarbamate: A solution of 22B (0.5 g,1.553 mmol), tributyl(1-ethoxyvinyl)stannane (1.049 mL, 3.11 mmol), andbis(triphenylphosphine)palladium(II) chloride (0.109 g, 0.155 mmol) intoluene (3 mL) in a sealed tube was heated at 110° C. After 3 h, thereaction was cooled to rt and concentrated to yield a residue. Theresidue was dissolved in THF (3 mL), followed by addition of 1 N HClsolution (5 mmol). The above mixture was then stirred at rt for 1 h andthen diluted with EtOAc. The EtOAc mixture was then washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude productwhich was purified by silica gel chromatography to obtain the desiredproduct (0.254 g, 69%) as a yellow solid. MS(ESI) m/z: 239.3 (M+H)⁺.

22D. 2-(4-((Methoxycarbonyl)amino)-2-nitrophenyl)-2-oxoacetic acid: To asolution of 22C (11.5 g, 48.3 mmol) in pyridine (48.3 mL) was addedselenium dioxide (8.04 g, 72.4 mmol) in portions. The reaction mixturewas then stirred under argon at 60° C. overnight and concentrated. Theresidue was pumped for several hours to make sure most pyridine wasremoved. To the solid was then added 1.0 N HCl (80 mL) and filtered toobtain a grayish solid which was dried in a vacuum-oven at 45° C.overnight. The grayish solid was then mixed with MeOH (200 mL) to yielda suspension which was then filtered and the filtrate was concentratedto give brownish foam (11.8 g, 79%) with still some residual pyridine init. MS(ESI) m/z: 269.0 (M+H)⁺.

22E. Methyl 2-(4-((methoxycarbonyl)amino)-2-nitrophenyl)-2-oxoacetate:To a red oil of 22D (11.8 g, 38.3 mmol) in DCM (150 mL) at 0° C. wasadded TEA (7.47 mL, 53.6 mmol) and the mixture was subjected tosonication to form a red-colored solution. To this mixture was thenadded methyl carbonochloridate (4.15 mL, 53.6 mmol) at 0° C. After 20min, the reaction mixture was diluted with DCM (300 mL), washed with 1 MHCl, saturated NaHCO₃ solution and brine. The organic phase was driedover MgSO₄, filtered and concentrated to give a red colored solid. Thecrude product was then purified by silica gel chromatography to yieldthe desired product (8.6 g, 80%) as light grayish powder. MS(ESI) m/z:283.0 (M+H)⁺.

22F. Methyl(4-(6-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-3-oxo-2,3-dihydropyridazin-4-yl)-3-nitrophenyl)carbamate:To a clear solution of 22A (1.16 g, 3.61 mmol) in EtOH (38.4 mL) at rtwas added K₂CO₃ (0.748 g, 5.42 mmol). The reaction mixture was stirredfor 2 h and then concentrated to yield a residue which was dried undervacuum for 1 h. To the residue was then added THF (30 mL) followed byaddition of a suspension of 22E (1.121 g, 3.97 mmol) in 8 mL of THFdropwise via an addition funnel After 3 h, hydrazine (0.567 mL, 18.05mmol) was added and the reaction was stirred at rt for 4 days. Thereaction mixture was then diluted with EtOAc, washed with 1 N HCl andbrine. The organic layer was then dried over MgSO₄, filtered, andconcentrated to give the crude product that was purified by silica gelchromatography to give the desired product (0.48 g, 29%) as a lightorange solid. MS(ESI) m/z: 460.0 (M+H)⁺.

22G. (S)-Methyl(4-(6-(1-aminobut-3-en-1-yl)-3-chloropyridazin-4-yl)-3-nitrophenyl)carbamate:To a solution of 22F (2.2 g, 4.79 mmol) in MeOH (23.94 mL) was added HCl(4 M in Dioxane) (5.186 mL, 20.74 mmol) and stirred at rt for 6 h. Thereaction mixture was then concentrated to yield a brownish solid. To thebrownish solid was added ACN (23.94 mL) and phosphoryl trichloride(13.39 mL, 144 mmol), and the reaction mixture was heated at 80° C.overnight. After overnight stirring, the reaction mixture wasconcentrated and dried under vacuum overnight. The crude mixture wasthen cooled down to 0° C., followed by addition of 1 N HCl (20 mL) toquench the reaction. Neutralized the mixture with 1 N NaOH and extractedwith EtOAc (2×). The organic layers were then combined, washed withbrine, dried and concentrated to give a brownish solid as the desiredproduct (1.03 g, 57%). MS(ESI) m/z: 377.9 (M+H)⁺.

22H. Methyl(4-(6-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-3-chloropyridazin-4-yl)-3-nitrophenyl)carbamate:To a solution of 22G (1.03 g, 2.73 mmol) in DCM (27.3 mL) at 0° C. wasadded TEA (1.140 mL, 8.18 mmol) and Boc₂O (0.760 mL, 3.27 mmol). Thereaction was then stirred at 0° C. for 10 min and then was slowlyallowed to warm to rt and stirred overnight. The crude product wasconcentrated and purified by silica gel chromatography to isolate thedesired product (414 mg, 36%) as orange colored foam. MS(ESI) m/z: 477.9(M+H)⁺.

22I. Methyl(3-amino-4-(6-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-3-chloropyridazin-4-yl)phenyl)carbamate:To a mixture of 22H (472 mg, 0.988 mmol) and iron powder (276 mg, 4.94mmol) in acetic acid (7.407 mL) was added H₂O (2.469 mL) and heated at70° C. for 1 h. The reaction mixture was then cooled down using anice-H₂O bath, followed by neutralization with 10 N NaOH (aq), and atfinal stage concentrated NaHCO₃ solution was used to adjusted pH to 7-8.The reaction mixture was then extracted with EtOAc (3×) and the combinedEtOAc layers were further washed with brine, dried over MgSO₄, filtered,concentrated and purified by silica gel chromatography. The purifiedproduct was then subjected to chiral HPLC separation using CHIRALPAK® ADcolumn and 40% isopropanol/60% heptane) mixture as mobile phase. Twopeaks were seen eluting and peak 1 was designated as Diastereomer A(22Ia) and peak 2 was designated as Diastereomer B (22IB) (144 mg, 32%).MS(ESI) m/z: 447.8 (M+H)⁺.

Example 22. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 22 was made in the same way as Example 1 by replacing1F with 221 followed by substituting Intermediate 2 for Intermediate 14at the last coupling step. The coupling reagent used in the last stepwas EDC/HOBt and the desired product was isolated as a homochiralcompound. ¹H NMR (400 MHz, MeOD) δ 9.56 (br. s., 1H), 9.22 (br. s., 1H),7.82 (d, J=1.8 Hz, 1H), 7.62 (d, J=8.6 Hz, 4H), 7.11-7.01 (m, 1H), 5.81(dd, J=11.9, 2.8 Hz, 1H), 5.40 (dd, J=12.3, 5.4 Hz, 1H), 4.45-4.36 (m,1H), 3.85-3.74 (m, 4H), 2.90-2.48 (m, 2H), 2.39-2.21 (m, 2H), 2.12-1.99(m, 1H), 1.94-1.78 (m, 1H), 1.56-1.20 (m, 2H), 0.97 (d, J=6.8 Hz, 3H),0.67 (br. s., 1H) ppm. MS(ESI) m/z: 592.1 (M+H)⁺. Analytical HPLC(Method A) RT=8.25 min.

Example 23 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt (Diastereomer A)

Example 23. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 23 was made in the same way as Example 22 by replacing221B with 22IA. ¹H NMR (500 MHz, MeOD) δ 9.67 (s, 1H), 9.43 (br. s.,1H), 8.75-8.70 (m, 1H), 8.27-8.18 (m, 2H), 7.82 (ddd, J=8.3, 6.8, 1.7Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.63-7.49 (m, 4H), 7.37 (td, J=8.2, 1.5Hz, 1H), 5.43-5.29 (m, 1H), 3.84-3.77 (m, 1H), 2.82-2.69 (m, 1H),2.26-2.00 (m, 2H), 1.96-1.83 (m, 1H), 1.66-1.42 (m, 2H), 0.98 (d, J=6.9Hz, 3H), 0.50 (d, J=11.8 Hz, 1H) ppm. MS(ESI) m/z: 592.0 (M+H)⁺.Analytical HPLC (Method A) RT=8.27 min.

Example 24 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

24A. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-3-(2-ethylbut-3-enoyl)amino)phenyl)carbamate:Compound 24A was prepared following the procedure described in 2I byreplacing 2-methylbut-3-enoic acid with 2-ethylbut-3-enoic acid.Purification by normal phase chromatography gave 24A (0.412 g, 74%) as ayellow foam. MS(ESI) m/z: 509.3 (M+H)⁺.

24B. tert-Butyl methyl((4E,7S)-3-ethyl-2-oxo-2,3,6,7-tetrahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-7,15-diyl)biscarbamate(Diastereomer A) and 24C. tert-Butyl methyl((4E,7S)-3-ethyl-2-oxo-2,3,6,7-tetrahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-7,15-diyl)biscarbamate(Diastereomer B): Compounds 24B and 24C were prepared following theprocedure described in 1H, by replacing 1G with 24A. Purification bynormal phase chromatography gave 24C (peak 1, designated as DiastereomerB) [0.05 g, 16%, MS(ESI) m/z: 481.2 (M+H)⁺] and 24B (peak 2, designatedas Diastereomer A) [0.03 g, 10%, MS(ESI) m/z: 481.2 (M+H)⁺].

24D. tert-Butyl methyl((3R,7S)-3-ethyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-7,15-diyl)biscarbamate(Diastereomer B): To a degassed solution of 24C (0.05 g, 0.104 mmol) inMeOH (5 mL) was added 10% palladium on carbon (0.011 g, 10.40 μmol). Thereaction mixture was then stirred under H₂-balloon for 72 h. Thereaction mixture was then filtered through a pad of CELITE® rinsing withMeOH and DCM. The filtrate was concentrated to give 24D (0.045 g, 90%)as a brown solid. This material was used in the next step withoutfurther purification. MS(ESI) m/z: 483.3 (M+H)⁺.

Example 24. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 24 (0.006 g, 49%, yellow solid) was prepared followingthe procedures described in step 2M, by replacing 2L with 24D; followedby step 2N, by replacing Intermediate 11 with Intermediate 1. ¹H NMR(500 MHz, CD₃OD) δ 8.91 (d, J=2.2 Hz, 1H), 8.76 (d, J=6.1 Hz, 1H), 8.26(d, J=1.4 Hz, 1H), 7.93 (dd, J=6.1, 1.7 Hz, 1H), 7.86 (ddd, J=8.2, 6.7,1.4 Hz, 1H), 7.75 (ddd, J=8.2, 6.8, 1.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H),7.61 (d, J=2.2 Hz, 1H), 7.53 (dd, J=8.5, 2.2 Hz, 1H), 7.45 (td, J=8.3,1.4 Hz, 1H), 5.40 (dd, J=11.4, 5.9 Hz, 1H), 3.80 (s, 3H), 2.56-2.50 (m,1H), 2.33-2.24 (m, 1H), 2.09-2.01 (m, 1H), 1.96-1.88 (m, 1H), 1.73-1.46(m, 3H), 1.36-1.25 (m, 1H), 0.89 (t, J=7.4 Hz, 3H), 0.70-0.59 (m, 1H)ppm. MS(ESI) m/z: 606.3 (M+H)⁺. Analytical HPLC (Method A) RT=6.32 min.

Example 25 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 25. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 25 (0.013 g, 60%, yellow solid) was prepared followingthe procedures described in Example 24, by replacing 24C (DiastereomerB) with 24B (Diastereomer A) in step 24D. ¹H NMR (500 MHz, CD₃OD) δ 8.87(d, J=2.2 Hz, 1H), 8.69 (d, J=5.2 Hz, 1H), 7.87 (ddd, J=8.1, 6.6, 1.5Hz, 1H), 7.77-7.70 (m, 2H), 7.62-7.51 (m, 4H), 7.45 (td, J=8.2, 1.5 Hz,1H), 5.29 (dd, J=11.0, 5.0 Hz, 1H), 3.79 (s, 3H), 2.22-2.04 (m, 2H),1.92-1.76 (m, 3H), 1.61-1.38 (m, 3H), 1.03 (t, J=7.3 Hz, 3H), 0.91-0.78(m, 1H) ppm. MS(ESI) m/z: 606.2 (M+H)⁺. Analytical HPLC (Method A)RT=7.09 min.

Example 26 Ethyl(9R,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-5-[(methoxycarbonyl)amino]-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-9-carboxylate,2 TFA salt

26A. Ethyl2-((2-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((methoxycarbonyl)amino)phenyl)amino)pent-4-enoate:A mixture of 2G (954 mg, 2.313 mmol) and maleic acid (537 mg, 4.63 mmol)in ACN (20 mL) was stirred at rt under argon. To this mixture was thenadded ethyl 2-oxoacetate (0.458 mL, 2.313 mmol) (50% in toluene) andstirring was continued for 5 min. Next, allyltributylstannane (0.860 mL,2.78 mmol) was added to the above mixture and stirring was continued forovernight. After overnight stirring, the reaction mixture wasconcentrated in vacuo and diluted with EtOAc. The organic layer was thenwashed with 1 N NaOH (2×) solution and dried over MgSO₄. The organiclayer was then concentrated in vacuo to give the crude product which waspurified using silica gel chromatography to give the desired product(344 mg, 28%) as pale yellow oil. MS(ESI) m/z: 539.0 (M+H)⁺.

26B. Ethyl(4E,7S)-7-((tert-butoxycarbonyl)amino)-15-((methoxycarbonyl)amino)-2,3,6,7-tetrahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-2-carboxylate:Grubbs chemistry was performed as described before on 26A to yield thedesired product (0.315 g, 47%) as brown oil. MS(ESI) m/z: 510.9 (M+H)⁺.

26C. Ethyl(2R,7S)-7-((tert-butoxycarbonyl)amino)-15-((methoxycarbonyl)amino)-2,3,4,5,6,7-hexahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-2-carboxylate:A mixture of 26B (315 mg, 0.617 mmol), palladium (II) on carbon (131 mg,0.123 mmol) (10% on carbon), trifluoroacetic acid (0.047 mL, 0.617 mmol)and EtOH (7 mL) was stirred vigorously under a hydrogen balloon for 4 h.The reaction mixture was then filtered through a pad of CELITE® and thesolvent was removed in vacuo to give brown oil. The oil was diluted withEtOAc and washed with saturated Na₂CO₃ (2×) solution. The combinedorganics were dried over MgSO₄ and then concentrated to give the crudeproduct. The crude product was then purified using silica gelchromatography to give 26Ca (132 mg, 42%, Diastereomer A) as pale yellowoil and 26Cb was designated as Diastereomer B. MS(ESI) m/z: 513.1(M+H)⁺.

26D. Ethyl(2R,7S)-7-amino-15-((methoxycarbonyl)amino)-2,3,4,5,6,7-hexahydro-1H-8,12-(metheno)-1,9-benzodiazacyclotetradecine-2-carboxylate:A mixture of 26Ca (132 mg, 0.258 mmol), HCl (1288 μL, 5.15 mmol) (4 M indioxane) and EtOAc (2 mL) was stirred at rt. After stirring for 4.5 h,the solvent was removed in vacuo to give a light tan yellow solid as thedesired product (125 mg, 100%).

Example 26. Ethyl(9R,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-5-[(methoxycarbonyl)amino]-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-9-carboxylate,2 TFA salt (Diastereomer A): A mixture of1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid (3.82 mg,0.016 mmol), HOBT (4.42 mg, 0.029 mmol), EDC (5.53 mg, 0.029 mmol) andDIEA (0.025 mL, 0.144 mmol) in DMF (0.2 mL) was stirred at rt for 5 min.To the above mixture was then added 26D (7 mg, 0.014 mmol) and stirringwas continued for overnight. The reaction mixture was diluted with MeOHand purified by reverse phase HPLC to isolate the desired product (4.2mg, 33%) as light yellow solid. ¹H NMR (400 MHz, CD₃CN) δ 8.86 (br. s.,1H), 8.67 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.51 (d, J=2.7 Hz, 1H), 8.07(s, 1H), 7.88 (s, 1H), 7.69 (td, 1H, J=8, 2), 7.62 (dd, J=6.0, 1.6 Hz,1H), 7.44 (ddd, J=8.1, 6.7, 1.6 Hz, 1H), 7.35 (d, 1H, J=8), 7.30 (d,J=1.6 Hz, 1H), 7.22 (td, J=8.2, 1.6 Hz, 1H), 7.12 (dd, J=8.2, 2.2 Hz,1H), 5.35 (m, 1H), 3.85 (m, 2H), 3.62 (s, 3H), 2.93 (d, J=11.0 Hz, 1H),2.08 (m, 4H), 1.63 (m, 2H), 1.29 (m, 4H), 0.97 (t, J=7.1 Hz, 3H), 0.20(m, 1H) ppm. MS(ESI) m/z: 635.1 (M+H)⁺. Analytical HPLC (Method E)RT=7.39 min.

Example 27 MethylN-[(14S)-14-[2-(3-chlorophenyl)-4-oxo-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]-16-fluoro-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt

27A.2-(1-(3-Chlorophenyl)-4-(((7S)-9-fluoro-15-((methoxycarbonyl)amino)-3-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-8,12-(metheno)-1,10-benzodiazacyclotetradecin-7-yl)carbamoyl)-1H-pyrazol-3-yl)ethylmethanesulfonate: To a solution of Example 1 (0.01 g, 0.016 mmol) inpyridine (0.274 mL, 3.39 mmol) and DCM (0.5 mL) was added methanesulfonylchloride (1.23 μL, 0.016 mmol) and the reaction mixture wasstirred at rt overnight. The reaction mixture was then concentrated andtaken to the next step without further workup or purification. MS(ESI)m/z: 713.5 (M+H)⁺.

27B. Methyl((75)-7-(((3-(2-chloroethyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)carbonyl)amino)-9-fluoro-3-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-8,12-(metheno)-1,10-benzodiazacyclotetradecin-15-yl)carbamate:The crude product from step 27A (0.014 g, 0.020 mmol) was dissolved inDCM (1 mL) and transferred to a sealed tube where the DCM wasevaporated. To the above solid was then added DIEA (0.2 mL) and toluene(1 mL). The reaction flask was sealed and heated to 110° C. for 18 h.Aliquot LCMS shows no ring closure product but only the chloroethylproduct was observed. MS(ESI) m/z: 653.4 (M+H)⁺.

Example 27. MethylN-[(14S)-14-[2-(3-chlorophenyl)-4-oxo-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]-16-fluoro-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt: NaH (0.147 mg, 6.12 μmol) was added to a THF solution of 27B(4 mg, 6.12 μmol) and to this was added excess NaI and stirred at rtovernight. The reaction mixture was quenched with H₂O (0.1 mL),concentrated and purified directly on reverse phase HPLC. ¹H NMR (500MHz, MeOD) δ 8.61 (s, 1H), 8.38 (dd, J=9.3, 2.1 Hz, 1H), 8.23 (d, J=1.4Hz, 1H), 7.90 (s, 1H), 7.99 (m, 1H), 7.73 (dd, 1H), 7.72 (m, 1H), 7.55(m, 3H), 7.35 (dd, 1H), 5.75-5.71 (m, 1H), 3.77 (m, 1H), 3.76 (s, 3H),3.70 (m, 1H), 2.65 (m, 1H), 2.29 (m, 1H), 2.28 (m, 1H), 1.99 (m, 1H),1.85 (m, 1H), 1.65 (m, 1H), 1.40 (m, 1H), (d, J=6.9 Hz, 3H), 1.05 (m,1H) ppm. MS(ESI) m/z: 617.2 (M+H)⁺. Analytical HPLC (Method B) RT=11.7min.

Example 28 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-16-fluoro-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 28. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-16-fluoro-10-methyl-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 28 was made in the same way as Example 1 using 1Ib andreplacing Intermediate 9 with Intermediate 2. ¹H NMR (400 MHz, MeOD) δ9.47 (s, 1H), 8.75 (d, J=7.2 Hz, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.21 (s,1H), 8.05-8.18 (m, 2H), 7.81 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.58 (ddd,J=8.2, 6.7, 1.4 Hz, 1H), 7.45-7.54 (m, 3H), 7.35 (td, J=8.3, 1.7 Hz,1H), 5.18-5.31 (m, 1H), 3.78 (s, 3H), 2.55-2.68 (m, 1H), 2.09-2.23 (m,1H), 1.94-2.09 (m, 1H), 1.71-1.87 (m, 1H), 1.51-1.63 (m, 1H), 1.29-1.43(m, 1H), 1.06 (d, J=6.9 Hz, 4H) ppm. MS(ESI) m/z: 609.0 (M+H)⁺.Analytical HPLC RT=9.71 min (Method A).

Example 29 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19)-pentaen-5-yl]carbamate

29A. Methyl 4-(1,3-dioxolan-2-yl)-3-nitrobenzoate: To a solution ofmethyl 4-formyl-3-nitrobenzoate (9.0 g, 43.0 mmol) in toluene (150 mL)was added ethylene glycol (7.20 mL, 129 mmol) followed by p-TsOH (0.409g, 2.152 mmol) and the reaction mixture was heated at refluxtemperatures with azeotropic removal of H₂O using a Dean-Stark trap for4 h. The reaction mixture was then cooled and diluted with DCM. The DCMlayers were then washed with saturated NaHCO₃ solution. The organiclayer was dried (MgSO₄), filtered, and concentrated to yield a residue.The residue was dissolved in minimal quantity of DCM and purified bysilica gel chromatography to yield the desired product (8.53 g, 78%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.27 (d, J=8.2Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 6.38 (s, 1H), 4.00 (dt, J=3.8, 1.9 Hz,2H), 3.94 (dt, J=3.8, 1.9 Hz, 2H), 3.91 (s, 3H) ppm.

29B. 4-(1,3-Dioxolan-2-yl)-3-nitrobenzoic acid: Lithium hydroxidemonohydrate (5.67 g, 135 mmol) was added to a solution of 29A (11.4 g,45.0 mmol) in THF (120 mL), MeOH (120 mL) and H₂O (40.0 mL). The abovemixture was then heated to 50° C. After 1 h, the heating was reduced tort and stirring was continued for overnight. To the reaction mixture wasthen added H₂O (50 mL) and the organics were concentrated. The remainingaqueous layer was made acidic with 1.0 N HCl solution to precipitate outthe solids. The solids were collected by filtration, washed with H₂O anddried under vacuum overnight. ¹H NMR (400 MHz, DMSO-d₆) δ 13.68 (br. s.,1H), 8.36 (d, J=1.5 Hz, 1H), 8.25 (dd, J=8.1, 1.3 Hz, 1H), 7.88 (d,J=8.1 Hz, 1H), 6.38 (s, 1H), 4.05-3.89 (m, 4H) ppm.

29C. Methyl (4-(1,3-dioxolan-2-yl)-3-nitrophenyl)carbamate: To asolution of 29B (6.77 g, 28.3 mmol) in THF (100 mL) was added TEA (7.89mL, 56.6 mmol) dropwise in THF (25 mL) at −5° C. in a ice-salt bath. Thetemperature was maintained at −5° C., and a solution of ethylchloroformate (3.25 mL, 34.0 mmol) in THF (30 mL) was added dropwiseover 10 minutes. After stirring for an additional 30 minutes, a coldsolution of sodium azide (3.68 g, 56.6 mmol) in H₂O (12.5 mL) was addeddropwise. After stirring for additional 1 hour, the reaction mixture wasconcentrated in vacuo (without heating). The oily residue was dissolvedin the Et₂O (100 mL), washed with H₂O, brine, and dried over sodiumsulfate, filtered, and concentrated (without heating) to give the acylazide. This material was dissolved in toluene (100 mL) and heated to110° C. After 1 h, the temperature was lowered to 80° C., MeOH (60 mL)was added, and heating was continued for overnight. The reaction mixturewas concentrated and purified by silica gel chromatography to yield thedesired product (5.01 g, 66%) as amber solid. ¹H NMR (400 MHz, DMSO-d₆)δ 10.21 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 2H), 6.22 (s,1H), 3.95-3.90 (m, 4H), 3.69 (s, 3H) ppm.

29D. Methyl (4-formyl-3-nitrophenyl)carbamate: 29C (5.00 g, 18.64 mmol)was added to a solution of TFA (27 mL) and H₂O (3 mL) and stirred at rt.After 3 h, the reaction mixture was concentrated and the residue waspartitioned between H₂O and EtOAc. The organic layer was then washedwith saturated sodium bicarbonate solution, brine, dried over sodiumsulfate, filtered, and concentrated to give a light yellow solid as thedesired product (3.83 g, 92%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s,1H), 10.09 (s, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H),7.86-7.81 (m, 1H), 3.74 (s, 3H) ppm.

29E. (S)-tert-Butyl 1-(dimethoxyphosphoryl)-2-oxohex-5-en-3-ylcarbamate:To a solution of dimethyl methylphosphonate (13.98 mL, 131 mmol) in THF(87 mL) at −78° C. was added n-BuLi (82 mL, 131 mmol) slowly. Aftercompletion of addition, the reaction was stirred for 40 min and then asolution of (S)-methyl 2-(tert-butoxycarbonylamino)pent-4-enoate (6.0 g,26.2 mmol) in THF (30 mL) was added slowly. Stirring was continued foranother 40 min at −78° C. The reaction mixture was then quenched byadding H₂O (2.357 mL, 131 mmol). The reaction mixture was diluted withEtOAc (100 mL) and the layers were separated. The organic layer waswashed with 1 M HCl, saturated NaHCO₃ solution, brine, dried over MgSO₄,filtered, and concentrated to give a clear oil. The crude product wasfinally purified using silica gel chromatography to give the desiredproduct (7.46 g, 89%) as a colorless oil. MS(ESI) m/z: 343.9 (M+Na)⁺. ¹HNMR (500 MHz, CDCl₃) δ 5.63-5.76 (1H, m), 5.08-5.17 (2H, m), 4.33-4.43(1H, m), 3.80 (3H, d, J=2.20 Hz), 3.77 (3H, d, J=2.20 Hz), 3.28-3.37(1H, m), 3.05-3.16 (1H, m), 2.58-2.69 (1H, m), 2.42 (1H, dt, J=14.58,7.29 Hz), 1.43 (9H, s) ppm.

29F. Methyl(4-((1E,4S)-4-((tert-butoxycarbonyl)amino)-3-oxohepta-1,6-dien-1-yl)-3-nitrophenyl)carbamate:To a vigorously stirred solution of 29E (4.47 g, 13.92 mmol) and 29D(2.6 g, 11.60 mmol) in THF (anhydrous) (115 mL) and EtOH (absolute)(1.148 mL) under nitrogen was added portion wise K₂CO₃ (anhydrous) (2.56g, 18.56 mmol) at 0° C. The reaction mixture was allowed to warm to rtand then the mixture was heated at 55° C. The reaction mixture was thenfiltered with the aid of EtOAc and the filtrate evaporated to a residuewhich was dissolved in a small amount of methylene chloride and purifiedby normal phase chromatography to give the desired product (4.38 g, 90%)as a yellow solid. MS(ESI) m/z: 420.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 10.36 (s, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),7.83-7.73 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.02 (d, J=15.9 Hz, 1H), 5.77(ddt, J=17.0, 10.2, 6.7 Hz, 1H), 5.16-5.01 (m, 2H), 4.32 (td, J=8.5, 4.9Hz, 1H), 3.71 (s, 3H), 2.34-2.23 (m, 1H), 1.36 (s, 9H) ppm.

29G. Methyl(4-(6-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-2-oxo-1,2-dihydropyridin-4-yl)-3-nitrophenyl)carbamate:To a solution of 29F (3.0 g, 7.15 mmol) and1-(2-ethoxy-2-oxoethyl)pyridinium bromide (1.189 g, 7.15 mmol) in EtOH(130 mL), was added ammonium acetate (11.03 g, 143 mmol) portionwise.After 15 min, the mixture was stirred at 75° C. The reaction mixture wasthen concentrated and dissolved in EtOAc. The organic layer was thenwashed with 1.0 N HCl, H₂O, saturated sodium bicarbonate solution andfinally by brine. The organic phase was dried over sodium sulfate,filtered and concentrated to yield a residue which was purified bynormal phase chromatography to isolate the desired product (2.2 g, 67%)as a brown solid. MS(ESI) m/z: 459.3 (M+H)⁺.

29H. Methyl(3-amino-4-(6-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)carbamate:To a solution of 29G (2.9 g, 6.33 mmol) in MeOH (120 mL) was addedammonium chloride (0.677 g, 12.65 mmol) and zinc (4.14 g, 63.3 mmol).The suspension was stirred for 1 hour at rt and then at 65° C. forovernight. The suspension was filtered hot through a plug of CELITE® andthe filter cake was washed with hot MeOH. The filtrate was concentratedand dried under vacuum to give a yellowish brown solid. This residue wasre-dissolved in EtOAc (with 10% MeOH), washed with saturated sodiumbicarbonate solution and brine. The organic layer was then dried oversodium sulfate, filtered and concentrated. The crude product was thensubjected to chiral separation using chiral AD-H 21×250 mm, using amixture of 35% (50/50 EtOH, i-PrOH and 0.1% DEA) and 65% CO₂ with a flowrate of 70 mL/min and 150 bar at 40° C. Each separated enantiomer wasconcentrated separately and the resulting solid placed under vacuumovernight. Analytical data corresponds to the desired product (1.12 g,41%, 29Ha). MS(ESI) m/z: 429.2 (M+H)⁺. ¹H NMR: (400 MHz, MeOD) δ 7.03(d, J=8.6 Hz, 2H), 6.79 (dd, J=8.3, 2.0 Hz, 1H), 6.48 (d, J=5.6 Hz, 2H),5.91-5.74 (m, 1H), 5.22-5.09 (m, 2H), 4.58-4.48 (m, 1H), 3.75 (s, 3H),2.55 (t, J=5.9 Hz, 1H), 2.53-2.43 (m, 1H), 1.45 (br. s., 9H) ppm. Theother isomer (29Hb) is also separately isolated.

29I. Methyl(4-(6-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-2-oxo-1,2-dihydropyridin-4-yl)-3-((2-methylbut-3-enoyl)amino)phenyl)carbamate:Isobutyl chloroformate (0.956 g, 7.00 mmol) was added to2-methylbut-3-enoic acid (0.701 g, 7.00 mmol) and 4-methylmorpholine(0.770 mL, 7.00 mmol) in THF (33.3 mL) at 0° C. under a nitrogenatmosphere and stirred for 3 h. The resulting solids were filtered offand the filtrate was used directly for next step. To a round bottomflask containing the mixed anhydride, 29H (0.200 g, 0.467 mmol) and4-methylmorpholine (0.770 ml, 7.00 mmol) in DMF (6 mL) was addedportionwise (1 mL) every ten minutes over 1 h. The reaction mixture wasthen stirred at rt. After 3 d, the reaction mixture was partitionedbetween EtOAc and 1.0 NaOH (20 mL). The organic layer was washed with1.0 N NaOH, H₂O, 1.0 N HCl solution, H₂O, and brine. The organic layerwas dried, filtered and concentrated. The crude product was againdissolved in THF (20 mL) and treated with NaOH (10 mL, 10.00 mmol).After stirring for 1 h, the reaction mixture was concentrated andpurified using reverse phase HPLC to give the desired product (0.09 g,38%). MS(ESI) m/z: 511.4 (M+H)⁺.

29J. tert-Butyl methyl((7S)-3-methyl-2,10-dioxo-2,3,4,5,6,7,9,10-octahydro-1H-12,8-(metheno)-1,9-benzodiazacyclotetradecine-7,15-diyl)biscarbamate:A solution of 29I (90 mg, 0.176 mmol) in DCE (anhydrous) (9793 μL) in amicrowave vial was degassed for 15 minutes. To this solution was thenaddedtricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride(60.0 mg, 0.071 mmol) and the mixture was heated to 120° C. for 30 minunder microwave conditions. The reaction mixture was then concentratedand purified by reverse phase HPLC. Fractions for diastereomer 29J1(minor; Peak 1; more polar RT (by ACN PREP)=3.776 minutes) anddiastereomer 29J2 (major; Peak 2; less polar RT (by ACN PREP)=3.978minutes) were concentrated. Recovered 29J1 (8.2 mg, 19%) and 29J2 (14.8mg, 35%) after Grubbs macrocyclization. Each diastereomer was taken onto PtO₂ reduction by dissolution with EtOH (10 mL) in two separatehydrogenation vessels, treatment to each with equal amount ofplatinum(IV) oxide (12.01 mg, 0.053 mmol), and exposed to hydrogen gas(55 psi) overnight. The reactions were filtered, concentrated, andcarried forward to the next reaction without further purification. Finalsaturated analogs 29J3 (8.4 mg, 20%) and 29J4 (13.8 mg, 32%) wererecovered as brown films. MS(ESI) m/z: 485.3 (M+H)⁺ for bothdiastereomers.

Example 29. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19)-pentaen-5-yl]carbamate:Example 21 was prepared in the same way as Example 1 by subjecting 29J4to Boc deprotection followed by T3P coupling using the free amine andIntermediate 1. The crude reaction mixture was purified by reverse phaseHPLC. ¹H NMR (500 MHz, MeOD) δ 8.88 (d, J=2.2 Hz, 1H), 7.86 (ddd, J=8.1,6.6, 1.5 Hz, 1H), 7.76-7.71 (m, 1H), 7.52-7.40 (m, 4H), 6.67 (d, J=1.1Hz, 1H), 6.52 (d, J=1.1 Hz, 1H), 5.17 (dd, J=10.7, 6.6 Hz, 1H), 3.78 (s,3H), 2.79 (d, J=5.5 Hz, 1H), 2.05-1.94 (m, 2H), 1.79-1.58 (m, 3H),1.37-1.25 (m, 1H), 1.11-1.05 (m, 3H), 1.04 (d, J=7.2 Hz, 3H), 0.96-0.88(m, 1H) ppm. MS(ESI) m/z: 608.4 (M+H)⁺. Analytical HPLC (Method A)RT=6.27 min.

Example 30 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19)-pentaen-5-yl]carbamate

MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19)-pentaen-5-yl]carbamate:Example 30 is made the same way as with Example 29 by replacing 29J4with 29J3. ¹H NMR (500 MHz, MeOD) δ 8.90 (d, J=2.2 Hz, 1H), 7.88 (ddd,J=8.3, 6.6, 1.7 Hz, 2H), 7.76 (ddd, J=8.2, 6.8, 1.5 Hz, 1H), 7.54-7.44(m, 5H), 6.57 (s, 1H), 6.47 (s, 1H), 5.11 (dd, J=10.6, 6.2 Hz, 1H), 3.80(s, 3H), 2.41-2.30 (m, 1H), 2.10-1.93 (m, 3H), 1.87-1.78 (m, 1H),1.58-1.49 (m, 1H), 1.39-1.32 (m, 1H), 1.31-1.28 (m, 3H), 1.21-1.04 (m,1H) ppm. MS(ESI) m/z: 608.4 (M+H)⁺. Analytical HPLC (Method A) RT=6.23min.

Example 31 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 31. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 31 was prepared the same way as Example 2 by replacing4-bromopicolinaldehyde with 2-bromoisonicotinaldehyde and substitutingIntermediate 11 with Intermediate 2. Also, the acid chloride was used instep 2H instead of the acid in the coupling step. Unfortunately withExample 31, chiral resolution was not achieved as with Example 1 at step1I and hence the final compound was a diastereomeric mixture. ¹H NMR(500 MHz, CD₃CN) δ 8.60 (m, 1H), 8.42 (m, 1H), 8.22 (s, 1H), 8.02 (m,1H), 7.91 (m, 1H), 7.70 (ddd, J=8.4, 7.0, 1.7 Hz, 1H), 7.62 (m, 1H),7.37 (m, 2H), 7.23 (td, J=8.2, 1.5 Hz, 1H), 4.98 (m, 1H), 3.64, 3.66(2s, 3H), 2.55 (m, 2H), 1.98 (m, 1H), 1.71 (m, 4H), 1.33 (m, 5H), 1.08(d, J=6.9 Hz, 0.3H), 0.81 (d, J=6.9 Hz, 2.7H), 0.49 (m, 1H) ppm. MS(ESI)m/z: 591.1 (M+H)⁺. Analytical HPLC (Method E) RT=6.00 min.

Example 32 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-16-fluoro-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 32. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-16-fluoro-9-oxo-8,17-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 32 was made in the same way as Example 21 by using 1Finstead of starting with 21A. ¹H NMR (400 MHz, MeOD) δ 8.68 (d, J=1.9Hz, 1H), 8.22 (s, 1H), 8.14 (d, J=1.7 Hz, 1H), 8.07 (dd, J=9.4, 2.2 Hz,1H), 7.81 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.58 (ddd, J=8.2, 6.7, 1.7 Hz,1H), 7.45-7.55 (m, 3H), 7.36 (td, J=8.2, 1.5 Hz, 1H), 5.23 (dd, J=11.0,5.5 Hz, 1H), 3.78 (s, 3H), 2.39-2.55 (m, 1H), 2.08-2.23 (m, 1H),1.94-2.08 (m, 2H), 1.60-1.84 (m, 2H), 1.35-1.50 (m, 1H), 0.99-1.21 (m,1H) ppm. MS(ESI) m/z: 594.9 (M+H)⁺. Analytical HPLC RT=9.18 min (MethodA).

Example 33 MethylN-[(12E,15S)-15-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9,18-dioxo-8,17-diazatricyclo[14.3.1.0^(2,7)]icosa-1(19),2,4,6,12,16(20)-hexaen-5-yl]carbamate,TFA salt

33A. Methyl(4-(6-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-2-oxo-1,2-dihydropyridin-4-yl)-3-(pent-4-enoylamino)phenyl)carbamate:To a solution of 29H (115.4 mg, 0.269 mmol) in DCM (40 mL) was addedpyridine (0.109 mL, 1.347 mmol). The flask was placed under nitrogen andthe mixture cooled to 0° C. To this mixture was then added pent-4-enoylchloride (0.104 mL, 0.943 mmol) and the mixture was stirred for 10minutes at the same temperature and the reaction mixture was slowlyallowed to warm to rt and stirred at rt. After stirring for overnight,the reaction mixture was concentrated under reduced pressure and theresulting yellow residue was taken up in THF and 1 N NaOH (5:2, 7 mL)and stirred at 30° C. for 1.5 h to effect hydrolysis of o-acylatedintermediate to desired product. The reaction mixture was diluted withEtOAc and 1 N HCl was added to adjust the pH to 5-6 and the two phaseswere separated. The aqueous layer was further extracted with EtOAc (2×)and the combined organics washed with brine, dried (Na₂SO₄), filteredand evaporated to a residue. The crude product was then purified usingsilica gel chromatography to yield the desired product (97 mg, 70%) as atan solid. MS(ESI) m/z: 511.1 (M+H)⁺.

33B. tert-Butyl methyl((5E,8S)-2,11-dioxo-1,2,3,4,7,8,10,11-octahydro-13,9-(metheno)-1,10-benzodiazacyclopentadecine-8,16-diyl)biscarbamate:To a microwave vial was charged with 33A (96.6 mg, 0.189 mmol) andtricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride (64.4 mg, 0.076mmol). The vial was then capped, purged with argon and DCE(anhydrous—degassed) (10 mL) was added. The reaction mixture was thenheated to 120° C. for 30 min in the microwave. The mixture was thencooled to rt and washed with saturated NaHCO₃ followed by brine. Theorganic layers were then dried over Na₂SO₄, filtered and evaporated togive a dark solid. The crude product was then purified using reversephase HPLC to yield the desired product (24 mg, 26%) as a brown solid.MS(ESI) m/z: 483.0 (M+H)⁺.

Example 33. MethylN-[(12E,15S)-15-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9,18-dioxo-8,17-diazatricyclo[14.3.1.0^(2,7)]icosa-1(19),2,4,6,12,16(20)-hexaen-5-yl]carbamate,TFA salt: To a RBF containing 33B (4.1 mg, 8.50 μmol) was added HCl (4 Min dioxane) (2 mL, 8.00 mmol) and the reaction mixture was stirred undernitrogen at ambient temperature. After 1 h, the reaction mixture wasconcentrated and the crude product was taken to the next step withoutfurther purification. To a solution of the Boc deprotected product (3.59mg, 8.57 μmol) and DIEA (0.015 mL, 0.086 mmol) in DMF (anhydrous) (1.5mL) under nitrogen was added Intermediate 1(2.485 mg, 10.28 μmol)followed by T3P (7.65 μL, 0.013 mmol). The reaction mixture was stirredfor 20 min at ambient temperature. After 20 min, the reaction mixturewas diluted with MeOH to 2 mL and purified by reverse phase HPLC toyield the final desired product (2.4 mg, 43%) as a white solid. ¹H NMR(400 MHz, MeOD) δ 8.85 (d, J=2.2 Hz, 1H), 7.85-7.80 (m, 1H), 7.74-7.69(m, 1H), 7.55-7.52 (m, 1H), 7.44-7.39 (m, 2H), 7.30-7.27 (m, 1H), 6.40(d, J=1.4 Hz, 1H), 6.23 (d, J=1.1 Hz, 1H), 5.56-5.49 (m, 2H), 5.03-4.97(m, 2H), 3.74 (s, 3H), 2.69-2.60 (m, 3H), 2.51-2.38 (m, 5H). MS(ESI)m/z: 606.0 (M+H)⁺. Analytical HPLC RT=8.75 min.

Example 34 MethylN-[(10R,14S)-10-methyl-9-oxo-14-[1-(piperidin-4-yl)-1H-1,2,3-triazole-4-amido]-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,bis TFA salt

34A. (S)-2-(4-(Methoxycarbonylamino)-2-nitrophenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)pent-4-enoate: To a clear, colorlesssolution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (2.91 g,13.50 mmol) in DMF (33.7 mL) was added potassium hydrogen carbonate(1.622 g, 16.20 mmol). The reaction mixture was stirred for 20 min at rtand then cooled to 0° C. To the above reaction mixture was added asolution of Intermediate 16 (4.28 g, 13.50 mmol) in DMF (33.7 mL)dropwise and the reaction mixture was allowed to warm to rt and thenstirred at rt. After 18 h, the reaction was cooled to 0° C. and pouredinto ice-cold water. The aqueous layer was then extracted with EtOAc(3×) and the combined organic layers were washed with H₂O and brine. Theorganic layer was then dried over Na₂SO₄, filtered and concentrated toyield a yellow foam as(S)-2-(4-(methoxycarbonylamino)-2-nitrophenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)pent-4-enoate (6.09 g, 100%). MS(ESI) m/z:450.5 (M−H)⁺.

34B. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1H-imidazol-5-yl)-3-nitrophenyl)carbamate:To a 1000-mL RBF containing 34A (6.09 g, 13.49 mmol) was added xylene(135 mL) and the above mixture was sonicated to obtain a clear yellowsolution. To this solution was then added ammonium acetate (10.40 g, 135mmol) and the flask was equipped with a dean-stark trap and refluxcondenser. The reaction was warmed to 110° C. for 2 h and then raised to140° C. for 2 h. After a total of 4 h stirring, the reaction was stoppedand cooled to rt. The reaction mixture was then diluted with EtOAc andwashed with saturated NaHCO₃ (2×) solution and brine. The organic layerwas then dried over Na₂SO₄, filtered and concentrated to yield a browngum which was purified using silica gel chromatography to isolate abrown foam as the desired product (0.91 g, 16%). MS(ESI) m/z: 432.5(M+H)⁺.

34C. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-nitrophenyl)carbamate:A flame-dried 25 mL RBF was charged with NaH (0.092 g, 2.295 mmol) andthen THF (4.17 mL) was added to give a gray suspension. The abovesuspension was then cooled to 0° C. and then a clear, yellow solution of34B (0.9 g, 2.086 mmol) in THF (4.17 mL) was added dropwise. Thereaction mixture was then stirred at 0° C. for 30 min and then allowedto warm to rt and stirred for 0.5 h. The yellow suspension was againcooled to 0° C. and then SEM-Cl (0.370 mL, 2.086 mmol) was addeddropwise. The resulting cloudy reaction mixture was stirred at 0° C.After 1 h, the reaction was stopped by quenching with saturated NH₄Clfollowed by dilution with EtOAc. The layers were then separated and theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, andconcentrated to obtain a yellow oil which was purified by silica gelchromatography to yield the desired product as yellow foam (0.424 g,36%). MS(ESI) m/z: 562.0 (M+H)⁺. 1D NOE confirmed the regioisomericposition of SEM on the imidazole ring.

34D. (S)-Methyl4-(2-(1-Boc-aminobut-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-aminophenylcarbamate:To a solution of 34C (0.424 g, 0.755 mmol) in MeOH (5 mL) was added zinc(0.494 g, 7.55 mmol) and ammonium chloride (0.404 g, 7.55 mmol). Themixture was then stirred at 60° C. in a sealed tube. After 4 h, thereaction mixture was cooled to rt and the yellow suspension was dilutedwith DCM and washed with H₂O. The aqueous layer was extracted with 15%IPA in CHCl₃. The combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated. The crude product was thenpurified using silica gel chromatography to give an orange solid as thedesired product (0.31 g, 77%). MS(ESI) m/z: 532.4 (M+H)⁺.

34E. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-((trifluoroacetyl)amino)phenyl)carbamate:A solution of 34D (10.2 g, 19.18 mmol) and TEA (3.19 mL, 23.02 mmol) inEtOAc (50 mL) was cooled down to 0° C. under argon. To this solution wasadded 2,2,2-trifluoroacetic anhydride (2.97 mL, 21.10 mmol) dropwise viaa syringe pump. After completion of addition, the reaction mixture wasstirred for another 30 min at 0° C. The reaction mixture was thendiluted with EtOAc, washed with H₂O, brine and dried over MgSO₄. Thecrude product was then filtered to remove the solids and the organiclayer was concentrated and purified by silica gel chromatography toyield the desired product (10.69 g, 89%) as a yellow solid. MS(ESI) m/z:627.9 (M+H)⁺.

34F. (6S,E)-Benzyl6-((tert-butoxycarbonyl)amino)-6-(4-(4-((methoxycarbonyl)amino)-2-(2,2,2-trifluoroacetamido)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-methylhex-3-enoate:To a solution of 34E (3.3 g, 5.26 mmol) and Intermediate 17 (5.91 g,31.1 mmol) in DCM (80 mL) was added pTsOH (0.905 g, 5.26 mmol). Theabove solution was then bubbled with argon for 30 min. The reactionmixture was sealed, heated to 40° C. under argon for 10 min, and addedGrubbs II (1.5 g, 1.767 mmol) in 20 mL argon degassed DCM dropwise viasyringe pump over 3 h while maintaining the reaction temperature at 40°C. After overnight stirring, the reaction mixture was washed withconcentrated NaHCO₃ (aq) and brine. The organic layer was dried overMgSO₄, filtered and concentrated. The crude product was then purified bysilica gel chromatography to yield the desired product (1.93 g, 46%) asa yellow solid. MS(ESI) m/z: 790.4 (M+H)⁺.

34G.(65)-6-((tert-Butoxycarbonyl)amino)-6-(4-(4-((methoxycarbonyl)amino)-2-(2,2,2-trifluoroacetamido)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-methylhexanoicacid: A solution of 34F (1.76 g, 2.228 mmol) in MeOH (40 mL) wasvacuumed and refilled with argon. To this solution under argon was addedpalladium on carbon (10%) (500 mg, 0.470 mmol), vacuumed and refilledwith H₂ gas (3×). The reaction mixture was then stirred at rt under H₂balloon. After overnight stirring, the reaction mixture was filteredthrough CELITE®. The filtrate was concentrated and purified by silicagel chromatography to isolate the desired product (1.23 g, 79%) as abeige solid. MS(ESI) m/z: 702.1 (M+H)⁺.

34H.(6S)-6-(4-(2-Amino-4-((methoxycarbonyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-((tert-butoxycarbonyl)amino)-2-methylhexanoicacid: To a solution of 34G (1.656 g, 2.360 mmol) in MeOH (14 mL) wasadded LiOH (2 N aq) (7 mL, 14.00 mmol). The reaction mixture was sealedand heated at 60° C. After 1 h, the reaction mixture was cooled down onan ice H₂O bath, 1 N HCl (aq) was added to adjust pH to 6. The aqueouslayer was extracted with EtOAc (2×60 mL). The combined EtOAc layers werewashed with brine, dried over MgSO₄, filtered, and concentrated to yieldthe desired product (1.43 g, 100%) as a grayish solid. MS(ESI) m/z:606.3 (M+H)⁺.

34I. tert-Butyl methyl((3R,7S)-3-methyl-2-oxo-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6,7,9-octahydro-11,8-(azeno)-1,9-benzodiazacyclotridecine-7,14-diyl)biscarbamate:To a mixture of BOP (1141 mg, 2.58 mmol), DMAP (529 mg, 4.33 mmol) andDIEA (1.261 mL, 7.22 mmol) in DCM (300 mL) was added 34H (625 mg, 1.032mmol) in DMF (5 mL) dropwise via syringe pump. The reaction mixture wasstirred at rt for 2 days before transferred to a sealed vessel. Thereaction was heated at 50° C. for 48 h before cooling down to rt. Thereaction mixture was concentrated to small volume and to the residue wasadded EtOAc. The EtOAc layer was washed with 10% LiCl solution to removeDMF and the organic layers were dried over MgSO₄. The organic layer wasthen concentrated and purified by silica gel chromatography followed byreverse phase HPLC. Two major peaks were seen on HPLC and the first peakwas identified as the desired product (second peak is the other isomer)based on previous X-ray studies and stereochemistry is assigned based onprevious compounds. Isolated 132 mg (22%) of the desired product as awhite solid. MS(ESI) m/z: 588.1 (M+H)⁺.

34J. Methyl((3R,7S)-7-amino-3-methyl-2-oxo-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6,7,9-octahydro-11,8-(azeno)-1,9-benzodiazacyclotridecin-14-yl)carbamate:To a solution of 341 (120 mg, 0.204 mmol) in DCM (4 mL) was added TFA(0.8 mL, 10.38 mmol) and stirred at rt for 1 h. The reaction wasquenched with concentrated Na₂CO₃ aqueous solution followed byextraction with DCM and EtOAc. The organic layers were washed withbrine, dried over MgSO₄ and concentrated under vacuo to yield thedesired product (71 mg, 71%) as a yellow gum. MS(ESI) m/z: 488.3 (M+H)⁺.

Example 34. MethylN-[(10R,14S)-10-methyl-9-oxo-14-[1-(piperidin-4-yl)-1H-1,2,3-triazole-4-amido]-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,bis TFA salt: To a solution of 34J (23 mg, 0.047 mmol) in DMF (1 mL) wasadded1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-1,2,3-triazole-4-carboxylicacid (15.37 mg, 0.052 mmol), EDC (18.08 mg, 0.094 mmol), HOBT (14.45 mg,0.094 mmol) and TEA (0.066 mL, 0.472 mmol) and the reaction mixture wasstirred at rt overnight. The reaction mixture was concentrated andpurified on reverse phase HPLC to give the Boc protected product (29 mg,70%) as a white solid. To the above white solid (29.2 mg, 0.033 mmol) ina vial was added HCl (4 N in dioxane) (0.8 mL, 3.20 mmol) and thereaction mixture was heated at 75° C. for 1 h. The reaction mixture wascooled down to rt and concentrated. The crude product was then subjectedto reverse phase HPLC purification to yield the desired product (22 mg,81%) as a white solid. ¹H NMR (400 MHz, MeOD) δ 9.57 (s, 1H), 8.52 (s,1H), 7.57 (d, J=2.0 Hz, 1H), 7.52-7.38 (m, 2H), 5.38 (dd, J=10.4, 6.8Hz, 1H), 4.99-4.89 (m, 1H), 3.76 (s, 3H), 3.63-3.55 (m, 2H), 3.28-3.21(m, 1H), 2.77 (br. s., 1H), 2.51-2.19 (m, 4H), 2.17-2.02 (m, 1H),1.84-1.51 (m, 3H), 1.03 (d, J=7.1 Hz, 3H), 0.70 (d, J=12.1 Hz, 1H) ppm.MS(ESI) m/z: 536.4 (M+H)⁺. Analytical HPLC RT=5.02 min (Method A).

The following Examples in Table 3 were made by using the same procedureas shown in Example 34. The acids used in the final step are asindicated in the below table in the Intermediate section. Variouscoupling reagents could be used other than the one described in Example34 like BOP, PyBop, EDC/HOBt, HATU or T3P. Boc and SEM deprotection wasachieved prior to the final coupling unlike with Example 34 where theBoc group alone was removed in step 34J.

TABLE 3 RT, min Example # Stereochemistry R M + H Method A 35 Homochiral

581.0 6.74 36 Homochiral

580.2 6.79 37 Homochiral

595.3 5.81 38 Homochiral

599.1 6.99 39 Homochiral

595.3 5.68 40 Homochiral

594.4 5.59 41 Homochiral

576.3 5.54

The following Examples in Table 4 were made by using the same procedureas shown in Example 34 using the second isomer at step 34I. The acidsused in the final step are as indicated in the below table in theIntermediate section. Various coupling reagents could be used other thanthe one described in Example 34 such as BOP, PyBop, EDC/HOBt, HATU orT3P. Boc and SEM deprotection was achieved prior to the final couplingunlike with Example 34 where the Boc group alone was removed in step34J.

TABLE 4 RT, min Example # Stereochemistry R (Acid used) M + H Method A42 Homochiral

576.3 6.15 43 Homochiral

595.2 5.08 44 Homochiral

595.2 5.64

Example 45 Methyl(9R,14S)-14-[5-amino-1-(3-chlorophenyl)-1H-1,2,3-triazole-4-amido]-5-[(methoxycarbonyl)amino]-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylate,TFA salt

45A. Methyl(3-bromo-4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)carbamate:45A was prepared following the procedures described in step 34A, byreplacing Intermediate 16 with Intermediate 18; followed by step 34B and34C. MS(ESI) m/z: 597.1 (M+2+H)⁺.

45B:(R)-2-(2-(2-((S)-1-(tert-Butoxycarbonylamino)but-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-(methoxycarbonylamino)phenylamino)pent-4-enoicacid: To a mixture of 45A (2 g, 3.36 mmol), copper(I) iodide (0.064 g,0.336 mmol) and K₂CO₃ (1.160 g, 8.39 mmol) in a sealable tube were added(R)-2-aminopent-4-enoic acid (0.464 g, 4.03 mmol) and DMSO (6.72 mL).The reaction mixture was vacuumed and back-filled with argon for threetimes, then capped and heated at 90° C. for 18 h. The reaction mixturewas then cooled to rt and then diluted with EtOAc and H₂O. The aqueouslayer was extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated to givethe crude residue. A small amount of DCM (˜5 mL) was added to give abrown solution followed by addition of hexanes (˜300 mL) to result in ayellow suspension which was filtered. The solid was rinsed with hexaneand air-dried to yield the desired product as a yellow solid (1.8 g,85%). MS(ESI) m/z: 630.4 (M+H)⁺.

45C. (R)-Methyl2-(2-(2-((S)-1-(tert-butoxycarbonylamino)but-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-(methoxycarbonylamino)phenylamino)pent-4-enoate:To the solution of 45B (1.8 g, 2.86 mmol) in DMF (25 mL) was added K₂CO₃(0.395 g, 2.86 mmol) and MeI (0.179 mL, 2.86 mmol). The reaction mixturewas stirred at rt. After 20 h, the reaction mixture was diluted withEtOAc and H₂O. The aqueous layer was extracted with EtOAc and thecombined organic layers were washed with H₂O and brine. The organiclayer was then dried over Na₂SO₄, filtered and concentrated. The crudeproduct was then purified by silica gel chromatography to give brownfoam as the desired product (0.58 g, 32%). MS(ESI) m/z: 644.3 (M+H)⁺.

45D. Methyl(2R,7S)-7-((tert-butoxycarbonyl)amino)-14-((methoxycarbonyl)amino)-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6,7,9-octahydro-11,8-(azeno)-1,9-benzodiazacyclotridecine-2-carboxylate:A solution of 45C (0.58 g, 0.901 mmol) and Grubbs (II) (0.306 g, 0.360mmol) in DCE (22.52 mL) was heated at 120° C. under microwave conditionsfor 20 min and then cooled to rt. The reaction mixture was diluted withEtOAc and then washed with saturated NaHCO₃ solution and brine. Theorganic layer was then dried over MgSO₄, filtered, and concentrated. Thecrude product was then purified using silica gel chromatography to givea yellow solid as the desired product (0.128 g, 23%). MS(ESI) m/z: 616.4(M+H)⁺.

45E. Methyl(2R,7S)-7-((tert-butoxycarbonyl)amino)-14-((methoxycarbonyl)amino)-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6,7,9-octahydro-11,8-(azeno)-1,9-benzodiazacyclotridecine-2-carboxylate:To a solution of 45D (0.128 g, 0.208 mmol) in EtOAc (5 mL) was added TFA(0.032 mL, 0.416 mmol) and 10% palladium on carbon (0.022 g, 0.021mmol). Hydrogen was bubbled through the reaction mixture for 5 min, andthe reaction was stirred under H₂-balloon. After 17 h, EtOH (1 mL) wasadded to the reaction mixture, and the reaction was filtered through a0.45 μM GMF rinsing with MeOH (filtered twice) and concentrated. Thecrude product was then purified by reverse phase HPLC and isolated thedesired product as a solid (0.113 g, 64%). MS(ESI) m/z: 618.4 (M+H)⁺.

Example 45. Methyl(9R,14S)-14-[5-amino-1-(3-chlorophenyl)-1H-1,2,3-triazole-4-amido]-5-[(methoxycarbonyl)amino]-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylate,TFA salt: To a RBF was charged 45E (0.01 g, 0.016 mmol) followed byaddition of HCl (4 N in dioxane) (2 mL) and the reaction mixture washeated at 50° C. with small amount of cysteine for overnight. Thereaction mixture was then concentrated to a solid mass. In a separateflask, to Intermediate 8 (3.86 mg, 0.016 mmol) in DCM (1 mL) was addedVilsmeier reagent (0.1 mL) and the reaction was stirred at rt for 2 h.The above dried deprotected macrolide was stirred in DCM (1 mL) and tothis was cannulated the triazole acid chloride crude followed by theaddition of pyridine (0.4 mL) and stirring was continued for 2 h at rt.The reaction mixture was concentrated and purified via reverse phaseHPLC to yield the desired product (3 mg, 27%). ¹H NMR (400 MHz, MeOD) δ7.57-7.46 (m, 4H), 7.45-7.32 (m, 2H), 7.13 (m, 2H), 5.40-5.37 (dd,J=10.9, 7.1 Hz, 1H), 3.66 (s, 3H), 3.49 (s, 3H), 3.03-2.94 (m, 2H), 2.28(m, J=6.8 Hz, 1H), 1.75-1.66 (m, 4H), 1.23-1.14 (m, 2H), 0.32 (d, J=11.9Hz, 1H) ppm. MS(ESI) m/z: 608.2 (M+H)⁺. Analytical HPLC (Method A):RT=6.96 min.

The following Examples in Table 5 were made by using the same procedureas shown in Example 45. The acids used in the final step are asindicated in the below table in the Intermediate section. Variouscoupling reagents could be used other than the one described in Example45 like BOP, PyBop, EDC/HOBt, HATU or T3P.

TABLE 5 RT, min Example # Stereochemistry R M + H Method A 46 Homochiral

611.0 7.32 47 Homochiral

610.0 7.49 48 Homochiral

607.0 6.67 49 Homochiral

625.0 6.96 50 Homochiral

629.0 7.57

Example 51 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-8,16,18-triazatricyclo[130.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

51A. (S)-2-(4-(Methoxycarbonylamino)-2-nitrophenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)pent-4-enoate: To a clear, colorlesssolution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (2.91 g,13.50 mmol) in DMF (33.7 mL) was added potassium hydrogen carbonate(1.622 g, 16.20 mmol). The reaction mixture was then stirred for 20 minat rt and then cooled to 0° C. To the above cooled solution was thenadded a solution of Intermediate 16 (4.28 g, 13.50 mmol) in DMF (33.7mL) dropwise and the reaction mixture was allowed to warm to rt andcontinued to stir at rt. After 18 h, the reaction was cooled to 0° C.and poured into ice-cold H₂O. The aqueous layer was then extracted withEtOAc (3×) and the combined organic layers were washed with H₂O, brine,dried over Na₂SO₄, filtered, and concentrated to yield the desiredproduct as a yellow foam (6.09 g, 100%). MS(ESI) m/z: 450.5 (M−H)⁻.

51B. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1H-imidazol-5-yl)-3-nitrophenyl)carbamate:To a 1000-mL RBF containing 51A (6.09 g, 13.49 mmol) was added xylene(135 mL) and the reaction mixture was sonicated to obtain a clear yellowsolution. To the clear solution was then added ammonium acetate (10.40g, 135 mmol) and the flask was equipped with a dean-stark trap andreflux condenser. The reaction mixture was then heated 110° C. for 2 hand then at 140° C. for additional 2 h. The reaction was cooled to rtand diluted with EtOAc. The mixture was then washed with saturatedNaHCO₃ (2×) solution followed by brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel chromatography to yield the desired product as a brown foam (0.91 g,16%). MS(ESI) m/z: 432.5 (M+H)⁺.

51C. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-nitrophenyl)carbamate:A flame-dried 25 mL RBF was charged with NaH (0.092 g, 2.295 mmol) andthen THF (4.17 mL) was added to give a gray suspension. The suspensionwas cooled to 0° C. and then a clear, yellow solution of 51B (0.9 g,2.086 mmol) in THF (4.17 mL) was added dropwise. The reaction mixturewas stirred at 0° C. for 30 min and then allowed to warm to rt andstirred for 0.5 h. The yellow suspension was cooled to 0° C. and thenSEM-Cl (0.370 mL, 2.086 mmol) was added dropwise. The resulting cloudyreaction mixture was stirred at 0° C. After 1 h, the reaction wasstopped and quenched with saturated NH₄Cl solution followed by dilutionwith EtOAc. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were washed withsaturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated.The residue was then purified by silica gel chromatography to obtain thedesired product as a yellow foam (0.424 g, 36%). MS(ESI) m/z: 562.0(M+H)⁺. 1D NOE confirmed the regioisomeric position of SEM on theimidazole ring.

51D. (S)-Methyl4-(2-(1-Boc-aminobut-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-aminophenylcarbamate:To a solution of 51C (0.424 g, 0.755 mmol) in MeOH (5 mL) was added zinc(0.494 g, 7.55 mmol) and ammonium chloride (0.404 g, 7.55 mmol). Thecombined reaction mixture was stirred at 60° C. in a sealed tube for 4 hand then cooled to rt. The yellow suspension was diluted with DCM andwashed with H₂O. The aqueous layer was extracted with 15% IPA/CHCl₃ andthe combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated. The crude product was then purified usingsilica gel chromatography to give an orange solid as the desired product(0.31 g, 77%). MS(ESI) m/z: 532.4 (M+H)⁺.

51E. (S)-Methyl4-(2-(1-Boc-aminobut-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-(but-4-enamido)-phenylcarbamate:To a solution of but-3-enoic acid (0.024 g, 0.282 mmol) and 51D (0.15 g,0.282 mmol) in EtOAc (8.06 mL) was added DIEA (0.148 mL, 0.846 mmol).The reaction mixture was allowed to cool to −10° C. under argon. Next,T3P (0.332 mL, 0.564 mmol) was added and the reaction was allowed tostir for 5 min. The reaction mixture was then warmed to rt whilestirring under argon for 1 h. The crude product was then purified bysilica gel chromatography to yield a yellow solid (0.130 g, 77%).MS(ESI) m/z: 600.4 (M+H)⁺.

51F. tert-Butyl methyl((75)-2-oxo-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6,7,9-octahydro-11,8-(azeno)-1,9-benzodiazacyclotridecine-7,14-diyl)biscarbamate:51E was subjected to the macrocyclization protocol as describedpreviously to obtain the unsaturated macrocyclized product. The purifiedproduct was then subjected to hydrogenation using palladium on carbon(10%) (83 mg, 0.042 mmol). The flask was purged with nitrogen and to theflask was added EtOH (absolute) (10 mL) and EtOAc (10 mL). The flask wasagain purged with nitrogen (3×), evacuated and an atmosphere of hydrogen(approx. 55 psi) was introduced and the reaction was stirred at ambienttemperature. The reaction mixture was then filtered through a pad ofCELITE® with the aid of additional EtOAc and the solvent was evaporated.The desired product was obtained as a colorless solid (113 mg, 93%)which was used without further purification. MS(ESI) m/z: 574.5 (M+H)⁺.

Example 51. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: To a RBF charged with 51F (0.02 g, 0.035 mmol) was added 4 NHCl in dioxane (2 mL) and stirred at 70° C. for 2 h. The reactionmixture was then concentrated and dried under vacuum. The crude productwas then dissolved in DMF (2 mL) and to the above solution was addedIntermediate 1 (8.42 mg, 0.035 mmol) and T3P (0.040 mmol). The reactionmixture was again stirred at rt. After 2 h, the reaction mixture wasthen concentrated and purified via reverse phase HPLC to isolate thedesired product as a yellow solid (1.4 mg, 5%). ¹H NMR (400 MHz, MeOD) δ8.84 (dd, J=17.0, 2.2 Hz, 1H), 7.75 (td, J=7.3, 1.4 Hz, 1H), 7.68-7.55(m, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.44-7.23 (m, 5H), 5.27 (dd, J=10.7,6.3 Hz, 3H), 4.49-4.29 (m, 3H), 3.72-3.59 (m, 3H), 2.47-2.34 (m, 2H),2.32-2.12 (m, 3H), 2.09-1.89 (m, 4H), 1.69-1.08 (m, 13H), 1.31-1.08 (m,4H), 0.93 (s, 3H) ppm. MS(ESI) m/z: 567.0 (M+H)⁺. Analytical HPLC:RT=4.76 min (Method B).

Example 52 MethylN-[(14S)-14-[1-(3-chlorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

Example 52. MethylN-[(14S)-14-[1-(3-chlorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 52 was made in the same way as Example 51 except thefinal coupling step where it used the Vilsmeier protocol as describedwith Example 45. ¹H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 7.91 (t, 1H),7.78 (dd, 1H), 7.51-7.45 (m, 3H), 7.42-7.403 (m, 2H), 7.34 (dd, 1H),5.26 (m, 1H), 3.66 (s, 3H), 2.40 (m, 1H), 2.24 (m, 1H), 2.04-1.98 (m,2H), 1.65-1.53 (m, 2H), 1.38 (m, 1H), 0.98 (bm, 1H) ppm. MS(ESI) m/z:549.2 (M+H)⁺. Analytical HPLC: RT=4.90 min (Method B).

Example 53 MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate,TFA salt

Example 53. MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 53 was prepared in the same way as Example 24 bysubstituting 24A with 51D and using 4 N HCl in dioxane to deprotect Bocand SEM group at the same time before the final coupling step. Example53 was isolated as one of the early eluting diastereomers during thereduction of the macrocycle on prep HPLC. ¹H NMR (400 MHz, MeOD) δ 8.86(d, J=2.3 Hz, 1H), 7.93 (dd, J=8.2, 1.6 Hz, 1H), 7.78-7.90 (m, 1H),7.68-7.76 (m, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.28-7.48 (m, 3H), 7.09 (s,1H), 5.40-5.51 (m, 1H), 3.74 (s, 3H), 2.34-2.47 (m, 1H), 2.08-2.24 (m,1H), 1.86-2.02 (m, 2H), 1.50-1.79 (m, 2H), 1.33-1.50 (m, 2H), 1.23-1.32(m, 1H), 0.93 (t, J=7.5 Hz, 3H) ppm. MS(ESI) m/z: 595.2 (M+H)⁺.Analytical HPLC: RT=5.55 min (Method A).

Example 54 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate,TFA salt

Example 54. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-ethyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 54 was made in the same way as Example 53 and isolatedas the late eluting diastereomer during the reduction of the macrocycleon prep HPLC. ¹H NMR (400 MHz, MeOD) δ 9.62 (s, 1H), 8.93 (d, J=2.2 Hz,1H), 7.80-7.94 (m, 1H), 7.76 (ddd, J=8.3, 6.7, 1.5 Hz, 1H), 7.41-7.64(m, 5H), 5.31 (dd, J=10.3, 5.9 Hz, 1H), 3.78 (s, 3H), 2.25-2.45 (m, 2H),1.99-2.16 (m, 1H), 1.71-1.85 (m, 1H), 1.58-1.71 (m, 1H), 1.45-1.58 (m,1H), 1.18-1.41 (m, 3H), 1.02 (t, J=7.3 Hz, 3H) ppm. MS(ESI) m/z: 595.3(M+H)⁺. Analytical HPLC: RT=5.91 min (Method A).

Example 55 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-10-(propan-2-yl)-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

55A. tert-ButylN-[(1S)-1-(4-{4-[(methoxycarbonyl)amino]-2-[2-(propan-2-yl)but-3-enamido]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-en-1-yl]carbamate,TFA salt: 55A was prepared in the same way as 21B by substitutingbut-3-enoic acid with 2-isopropylbut-3-enoic acid and 21A with 51D. Thedesired product was isolated as a greenish oil. MS(ESI) m/z: 642.6(M+H)⁺.

Example 55. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-10-(propan-2-yl)-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 55 is prepared the same way as Example 24 bysubstituting 24A with 55A and using 4 N HCl in dioxane to deprotect Bocand SEM group at the same time before the final coupling step. Example55 was isolated as a diastereomeric mixture and so the final compound isa diastereomeric mixture. ¹H NMR (500 MHz, MeOD) δ 8.90 (m, 1H),7.85-7.84 (m, 1H), 7.71-7.69 (m, 1H), 7.60 (s, 1H), 7.55-7.41 (m, 4H),5.39 (dd, J=10.8, 6.9 Hz, 1H), 3.76 (s, 2H), 2.42 (m, 1H), 2.24-2.10 (m,2H), 1.81-1.47 (m, 4H), 0.98 (d, 3H), 0.90 (d, 3H) ppm. MS(ESI) m/z:609.2 (M+H)⁺. Analytical HPLC: RT=5.51 min (Method B).

Example 56 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-10-(propan-2-yl)-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

Example 56. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-10-(propan-2-yl)-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 56 was made in the same way as Example 55 and wasisolated as a single diastereomer during Grubbs macrocyclizationprotocol. It was isolated as the second peak following macrocyclizationand the final compound was homochiral. MS(ESI) m/z: 609.3 (M+H)⁺.Analytical HPLC (Method A) RT=7.34 min.

Example 57 Methyl N-[(12E,15S)-15-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-18-cyano-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate,TFA salt

57A. (S)-2-(4-(Methoxycarbonylamino)-2-nitrophenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)pent-4-enoate: To a clear, colorlesssolution of (S)-2-(tert-butoxycarbonyl amino)pent-4-enoic acid (2.91 g,13.50 mmol) in DMF (33.7 mL) was added potassium hydrogen carbonate(1.622 g, 16.20 mmol) and the reaction mixture was stirred for 20 min atrt and then cooled to 0° C. To the above mixture was then added asolution of Intermediate 16 (4.28 g, 13.50 mmol) in DMF (33.7 mL)dropwise and the reaction was allowed to warm to rt and stirring wascontinued. After 18 h, the reaction was stopped, cooled to 0° C. andpoured into ice-cold H₂O. The aqueous layer was then extracted withEtOAc (3×) and the combined organic layers were washed with H₂O andbrine. The organic layers were then dried over Na₂SO₄, filtered andconcentrated to give the desired product as a yellow foam (6.09 g,100%). MS(ESI) m/z: 450.5 (M−H)⁻.

57B. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1H-imidazol-5-yl)-3-nitrophenyl)carbamate:To a 1000-mL RBF containing 57A (6.09 g, 13.49 mmol) was added xylene(135 mL) and sonicated to obtain a clear yellow solution. To the aboveclear solution was then added ammonium acetate (10.40 g, 135 mmol) andthe flask was equipped with a dean-stark trap and reflux condenser. Thereaction mixture was then warmed to 110° C. for 2 h, then 140° C. foradditional 2 h. The reaction was cooled to rt and diluted with EtOAc.The mixture was then washed with saturated NaHCO₃ (2×) and brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by silica gel chromatography to yield a brownfoam as the desired product (0.91 g, 16%). MS(ESI) m/z: 432.5 (M+H)⁺.

57C. Methyl(4-(2-((1S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-nitrophenyl)carbamate:A flame-dried 25 mL RBF was charged with NaH (0.092 g, 2.295 mmol) andthen THF (4.17 mL) was added to give a gray suspension. The suspensionwas cooled to 0° C. and then a clear, yellow solution of 57B (0.9 g,2.086 mmol) in THF (4.17 mL) was added dropwise. The reaction mixturewas stirred at 0° C. for 30 min and then allowed to warm to rt andstirred for 0.5 h. The yellow suspension was cooled to 0° C. and thenSEM-Cl (0.370 mL, 2.086 mmol) was added dropwise. The resulting cloudyreaction mixture was then stirred at 0° C. After 1 h, the reactionmixture was quenched with saturated NH₄Cl solution followed by dilutionwith EtOAc. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were washed withsaturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated.The crude product was purified by silica gel chromatography to yield thedesired product as a yellow foam (0.424 g, 36%). MS(ESI) m/z: 562.0(M+H)⁺. 1D NOE confirmed the regioisomeric position of SEM on theimidazole ring.

57D. (S)-Methyl4-(2-(1-Boc-aminobut-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-aminophenylcarbamate:To a solution of 57C (0.424 g, 0.755 mmol) in MeOH (5 mL) was added zinc(0.494 g, 7.55 mmol) and ammonium chloride (0.404 g, 7.55 mmol). Themixture was stirred at 60° C. in a sealed tube for 4 h and then cooledto rt. The yellow suspension was diluted with DCM and then washed withH₂O. The aqueous layer was extracted with 15% IPA/CHCl₃. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was purified using silica gelchromatography to give an orange solid as the desired product (0.31 g,77%). MS(ESI) m/z: 532.4 (M+H)⁺.

57E. (S)-Methyl4-(2-(1-Boc-aminobut-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-(pent-4-enamido)-phenylcarbamate:To a solution of pent-4-enoic acid (0.028 g, 0.282 mmol) and 57D (0.15g, 0.282 mmol) in EtOAc (8.06 mL) was added DIEA (0.148 mL, 0.846 mmol).The reaction mixture was allowed to cool to −10° C. under argon. To theabove mixture was then added 1-propanephosphonic acid cyclic anhydridein EtOAc (0.332 mL, 0.564 mmol) and the reaction was allowed to stir for5 min. The reaction mixture was then warmed to rt while stirring underargon for additional 1 h and then it was concentrated. The crude productwas purified by silica gel chromatography to obtain a yellow solid(0.092 g, 53%). MS(ESI) m/z: 614.1 (M+H)⁺.

57F. tert-Butyl methyl((5E,8S)-2-oxo-10-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecine-8,15-diyl)biscarbamate:To a round bottom flask equipped with an argon bubbler was charged withfinely powdered 57E (1.0165 g, 1.656 mmol) and p-TsOH monohydrate (0.299g, 1.739 mmol). The flask was then purged with argon and DCM(anhydrous—degassed) (78 mL) was added followed by heating of thecolorless mixture at 40° C. The mixture was rapidly stirred at thistemperature until the reactants went into solution (˜5 min) after whicha solution oftricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride(0.070 g, 0.083 mmol) in DCM (anhydrous—degassed) (5.0 mL) was added atthe rate of ˜1 drop per second. Stirring was continued at 40° C. for 90minutes at which time an aliquot was removed. The mixture was thencooled to rt and washed with saturated NaHCO₃ solution and brine. Theorganic layer was then dried over Na₂SO₄, filtered, and concentrated togive a dark solid. The residue was purified using silica gelchromatography to give the desired product, as a mixture of the cis- andtrans-olefin isomers. The crude product was purified by reverse phaseHPLC to give two fractions, fraction 1 (trans-olefin isomer) andfraction 2 (cis-olefin isomer). Appropriate trans fractions wereevaporated to obtain the desired product as a colorless solid (404 mg,42%). MS(ESI) m/z: 586.5 (M+H)⁺.

57G.(5E,8S)-11-Bromo-10,15-dimethyl-8-(methylamino)-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-2-one:To a solution of 57F (0.225 g, 0.384 mmol) in CHCl₃ (5 mL) and ACN (5mL) was added NBS (0.082 g, 0.461 mmol) in a portion and the resultingsolution was stirred for 0.5 h at rt. The mixture was concentrated andpurified using silica gel chromatography to isolate the desired product(0.178 g, 70%). MS(ESI) m/z: 666.3 (M+H)⁺.

57H. tert-Butyl methyl((5E,8S)-11-cyano-2-oxo-10-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecine-8,15-diyl)biscarbamate:A solution of 57G (0.18 g, 0.271 mmol), zinc cyanide (0.019 g, 0.162mmol), DPPF (0.018 g, 0.032 mmol) and Pd₂(dba)₃-CHCl₃ (0.012 g, 0.014mmol) in DMF (2 mL) was degassed for 0.5 h under argon bubbling. Thesolution was then stirred at 130° C. for 0.5 h under microwaveconditions. The reaction mixture was then diluted with EtOAc and washedwith NaHCO₃ solution followed by brine. The organic layer was then driedover MgSO₄ and concentrated to give the crude product which was purifiedusing reverse phase HPLC to isolate the desired product (0.145 g, 88%).MS(ESI) m/z: 611.3 (M+H)⁺.

57I. Methyl((5E,8S)-8-amino-11-cyano-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl)carbamate:To a solution of 57H (145 mg, 0.237 mmol) in DCM (3 mL) was added TFA(0.500 mL) and the reaction was stirred at rt. After 2 h, the reactionmixture was concentrated to dryness. To the solid was added EtOAc andenough saturated NaHCO₃ (to make it basic). The aqueous layer was thenextracted with EtOAc (3×) and the combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated to give 421 (90mg, 100%) as a reddish solid. MS(ESI) m/z: 381.1 (M+H)⁺.

Example 57. MethylN-[(12E,15S)-15-[1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-18-cyano-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate,TFA salt: 57I (0.017 g, 0.045 mmol) was coupled with Intermediate 2(10.75 mg, 0.045 mmol) under the T3P (0.034 g, 0.045 mmol)/DIEA (7.81μL, 0.045 mmol) and DMF conditions as previously described. After 2 hthe reaction was concentrated and purified via reverse phase HPLC toyield the desired product as a white solid (6 mg, 22%). MS(ESI) m/z:603.1 (M+H)⁺. Analytical HPLC: RT=6.16 min (Method B).

Example 58 Methyl((12E,15S)-15-(((2-(3-chloro-2,6-difluorophenyl)-1H-imidazol-4-yl)carbonyl)amino)-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl)carbamate,2 TFA salt

Example 58. Methyl((12E,15S)-15-(((2-(3-chloro-2,6-difluorophenyl)-1H-imidazol-4-yl)carbonyl)amino)-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl)carbamate,2 TFA salt: Example 58 was made in the same way as Example 57 byreplacing Intermediate 2 with Intermediate 22. ¹H NMR (400 MHz, CDCl₃) δ7.95 (s, 1H), 7.73 (td, J=8.7, 5.5 Hz, 1H), 7.46 (s, 3H), 7.34-7.21 (m,1H), 5.73-5.58 (m, 1H), 5.51 (br. s., 1H), 5.31 (dd, J=10.3, 4.8 Hz,1H), 3.80 (s, 3H), 3.31-3.24 (m, 1H), 2.94 (d, J=13.8 Hz, 1H), 2.76-2.64(m, 1H), 2.61-2.38 (m, 3H) ppm. MS(ESI) m/z: 596.1 (M+H)⁺. AnalyticalHPLC: RT=4.24 min.

Example 59 Methyl((10R,14S)-14-(((1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)carbonyl)amino)-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl)carbamate,TFA salt

Example 59. Methyl((10R,14S)-14-(((1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)carbonyl)amino)-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl)carbamate,TFA salt: Example 59 was made in the same way as Example 31 by replacingintermediate 2 with intermediate 1. ¹H NMR (500 MHz, acetonitrile-d₃) δ8.63 (d, J=5.8 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.21 (s, 1H), 7.91 (s,1H), 7.87 (d, J=6.9 Hz, 1H), 7.83 (s, 1H), 7.70 (ddd, J=8.2, 6.7, 1.7Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.60 (ddd, J=8.3, 6.8, 1.7 Hz, 1H),7.42-7.38 (m, 2H), 7.34-7.27 (m, 2H), 5.11-5.02 (m, 1H), 3.64 (s, 3H),2.55 (td, J=6.4, 2.6 Hz, 2H), 1.99 (td, J=4.7, 2.3 Hz, 1H), 1.72-1.69(m, 1H), 1.47-1.39 (m, 2H), 1.36-1.30 (m, 2H), 0.83 (d, J=6.9 Hz, 3H).MS(ESI) m/z: 592.3 (M+H)⁺. Analytical HPLC (Method E) RT=5.97 min.

Example 60 Methyl((10S,14S)-14-(((1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)carbonyl)amino)-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl)carbamate,TFA salt

Example 60. Methyl((10S,14S)-14-(((1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)carbonyl)amino)-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl)carbamate,TFA salt: Example 60 is prepared the same way as Example 59 using theother isomer. ¹H NMR (500 MHz, CD₃CN) δ 8.46-8.52 (m, 1H), 7.86 (s, 1H),7.80 (br. s., 2H), 7.69 (d, J=8.25 Hz, 2H), 7.60 (ddd, J=1.51, 6.81,8.18 Hz, 1H), 7.48 (s, 1H), 7.26-7.38 (m, 4H), 7.14 (dd, J=1.65, 5.23Hz, 1H), 4.92-5.00 (m, 1H), 3.97 (q, J=7.15 Hz, 1H), 3.63 (s, 3H),2.11-2.18 (m, 1H), 1.91-1.96 (m, 1H), 1.62-1.76 (m, 2H), 1.07-1.13 (m,3H), 0.91-0.97 (m, 1H), 0.76-0.81 (m, 1H) ppm. MS(ESI) m/z: 592.2(M+H)⁺. Analytical HPLC (Method E) RT=6.00 min.

Example 61 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 61. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: To a vial containing Intermediate 25 (0.085 g, 0.335 mmol), 2M(0.2 g, 0.335 mmol), EDC (0.096 g, 0.503 mmol), HOBT (0.077 g, 0.503mmol), and DMF (4 mL) was added Hunig's base (0.293 mL, 1.677 mmol). Thereaction was stirred at rt overnight and then concentrated. The residuewas purified by reverse phase HPLC to yield the desired product (0.073g, 30%) as an off-white solid. ¹H NMR (500 MHz, MeOD) δ 8.69 (d, J=6.1Hz, 1H), 8.30 (s, 1H), 8.11 (d, J=1.1 Hz, 1H), 7.81 (dd, J=5.9, 1.8 Hz,1H), 7.71 (ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.57(d, J=1.9 Hz, 1H), 7.50 (dd, J=8.5, 2.2 Hz, 1H), 7.46 (ddd, J=8.0, 6.5,1.7 Hz, 1H), 7.40-7.36 (m, 1H), 5.24 (dd, J=11.4, 5.9 Hz, 1H), 3.77 (s,3H), 2.80-2.73 (m, 1H), 2.35 (d, J=1.1 Hz, 3H), 2.23-2.13 (m, 1H),2.02-1.90 (m, 2H), 1.65-1.46 (m, 2H), 0.97 (d, J=6.9 Hz, 3H), 0.55-0.44(m, 1H) ppm. MS(ESI) m/z: 605.2 (M+H)⁺. Analytical HPLC RT=5.96 min(Method A).

Example 62 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,2 TFA salt

Example 62. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,2 TFA salt: A clear, colorless solution of Intermediate 24 (0.012 g,0.045 mmol), 2M (Alternative, 2 HCl) (0.020 g, 0.045 mmol), EDC (0.013g, 0.068 mmol), HOBT (10.41 mg, 0.068 mmol), and Hunig's base (0.040 ml,0.227 mmol) in DMF (0.453 mL) was stirred at rt overnight. The reactionwas diluted with MeOH and purified by reverse phase HPLC to yield thedesired product (0.0172 g, 44%) as an off-white granular solid. ¹H NMR(500 MHz, MeOD) δ 8.71 (d, J=5.8 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.84(dd, J=5.9, 1.8 Hz, 1H), 7.81 (s, 1H), 7.72 (ddd, J=8.2, 6.7, 1.7 Hz,1H), 7.63 (d, J=8.5 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.50 (dd, J=8.4,2.1 Hz, 1H), 7.47-7.43 (m, 1H), 7.41-7.37 (m, 1H), 5.29 (dd, J=11.3, 6.1Hz, 1H), 3.77 (s, 3H), 2.81-2.73 (m, 1H), 2.32 (d, J=0.6 Hz, 3H),2.25-2.17 (m, 1H), 2.01-1.90 (m, 2H), 1.66-1.48 (m, 2H), 0.96 (d, J=7.2Hz, 3H), 0.53-0.42 (m, 1H) ppm. MS(ESI) m/z: 605.4 (M+H)⁺. AnalyticalHPLC RT=5.20 min (Method D).

Example 63 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 63. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: To a vial containing Intermediate 21 (10.7 mg, 0.042 mmol), 2M(0.025 g, 0.042 mmol), EDC (0.012 g, 0.063 mmol), and HOBT (9.6 mg,0.063 mmol) in DMF (0.5 mL) was added Hunig's base (0.037 mL, 0.210mmol). The reaction was heated at 55° C. for 2 h and then cooled to rt.The reaction mixture was diluted with MeOH and filtered. The filtratewas concentrated and purified by reverse phase HPLC to yield the desiredproduct (0.014 g, 46%) as a white solid. ¹H NMR (500 MHz, MeOD) δ 8.70(d, J=5.5 Hz, 1H), 7.92 (ddd, J=8.3, 6.9, 1.7 Hz, 1H), 7.81 (s, 1H),7.70 (td, J=7.4, 1.7 Hz, 1H), 7.58-7.45 (m, 4H), 7.39 (d, J=1.9 Hz, 1H),5.25 (dd, J=10.7, 5.8 Hz, 1H), 3.69 (s, 3H), 2.71-2.63 (m, 1H), 2.40 (s,3H), 2.05-1.96 (m, 1H), 1.90-1.77 (m, 2H), 1.46-1.24 (m, 2H), 0.83 (d,J=6.9 Hz, 3H), 0.31-0.19 (m, 1H) ppm. MS(ESI) m/z: 606.3 (M+H)⁺.Analytical HPLC RT=6.46 min (Method A).

The following Examples in Table 6 were made by using the same procedureas shown in Example 63. The acids used in the final step are asindicated in the below table in the Intermediate section. Variouscoupling reagents could be used other than the one described in Example63 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 6 RT, min Example # Stereochemistry R M + H Method 64 Homochiral

606.9 5.94 A 65 Homochiral

603.2 4.87 D 66 Homochiral

617.2 5.23 D 67 Homochiral

606.2 5.08 D 68 Homochiral

606.1 4.81 A 69 Homochiral

588.1 4.80 A 70 Homochiral

586.0 4.14 A 71 Homochiral

601.4 6.23 A 72 Homochiral

609.3 4.87 D 73 Homochiral

605.3 4.83 D 74 Homochiral

572.1 4.65 A 75 Homochiral

602.3 5.33 A 76 Homochiral

642.0 6.35 A

Example 77 MethylN-[(10R,14S)-14-[1-(2-fluoro-3-methoxyphenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

Example 77. MethylN-[(10R,14S)-14-[1-(2-fluoro-3-methoxyphenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 77 was made in the same way as Example 63 by usingIntermediate 30. ¹H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 7.61 (d, J=2.0Hz, 1H), 7.56-7.52 (m, 2H), 7.47-7.36 (m, 4H), 5.55-5.39 (m, 1H),4.06-3.92 (m, 3H), 3.99 (s, 3H), 3.79 (s, 3H), 2.79-2.77 (bm, J=10.6 Hz,2H), 2.69-2.64 (bm, 1H), 2.32 (m, 1H), 1.75 (m, 1H), 1.66 (bm, 2H), 1.08(d, 3H), 0.99 (bm, 1H). MS(ESI) m/z: 577.3 (M+H)⁺. Analytical HPLCRT=5.74 min (Method A).

The following Examples in Table 7 were made by using the same procedureas shown in Example 31. The acids used in the final step are asindicated in the below table in the Intermediate section. Variouscoupling reagents could be used other than the one described in Example2 like BOP, PyBop, EDC/HOBt or HATU. In step 2F methyl chloroformate canbe replaced with 3-methoxypropanoyl chloride.

TABLE 7 RT, min Example # Stereochemistry R R¹ M + H Method A 78Homochiral 10R

Me 606.6 6.39 79 Homochiral 10R

Me 624.6 6.07 80 Homochiral 10R

668.7 6.04 81 Homochiral 10R

Me 605.6 5.95 82 Homochiral 10S

649.6 5.80 83 Homochiral 10R

649.7 5.83 84 Homochiral 10R

Me 605.6 4.98 85 Homochiral 10R

Me 609.6 5.48

Example 86 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-16-fluoro-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 86. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-16-fluoro-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 86 was prepared the same way as Example 2 by replacing4-bromopicolinaldehyde with 2-bromo-5-fluoroisonicotinaldehyde andsubstituting Intermediate 11 with Intermediate 21. ¹H NMR (500 MHz,MeOD) δ 8.65 (d, J=2.8 Hz, 1H), 7.95 (d, J=6.3 Hz, 1H), 7.82 (ddd,J=8.2, 6.8, 1.5 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.61-7.52 (m, 2H),7.50-7.43 (m, 2H), 5.35 (dd, J=11.3, 5.8 Hz, 1H), 3.78 (s, 3H), 3.32 (m,3H), 2.71 (td, J=6.7, 2.5 Hz, 1H), 2.45 (d, J=0.6 Hz, 3H), 2.24-2.16 (m,1H), 2.14-2.05 (m, 1H), 1.97-1.86 (m, 1H), 1.74-1.62 (m, 1H), 1.55-1.43(m, 1H), 1.01 (d, J=7.2 Hz, 3H), 0.97-0.86 (m, 1H) ppm. MS(ESI) m/z:623.9 (M+H)⁺. Analytical HPLC RT=8.73 min (Method A).

Example 87 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-6-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

87A. MethylN-{3-amino-4-[2-(1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl)pyridin-4-yl]-2-fluorophenyl}carbamate:To a solution of 2H (50 mg, 0.121 mmol) in DMF (0.5 mL) was added Na₂CO₃(22 mg, 0.208 mmol), followed by Accufluor (50% in alumina) (143 mg,0.222 mmol). The reaction was stirred at rt for 40 min and concentrated.The residue was purified by reverse phase HPLC to isolate the desiredproduct (10 mg, 19%). MS(ESI) m/z: 431.1 (M+H)⁺.

87B. MethylN-[(10R,11E,14S)-14-{[(tert-butoxy)carbonyl]amino}-6-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl]carbamate(diastereomer mixture): 87B was made in the same way as 2J by replacing2H with 87A. MS(ESI) m/z: 485.1 (M+H)⁺.

87C. MethylN-[(10R,14S)-14-amino-6-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,HCl salt: To a solution of 87B (3.5 mg, 7.22 μmol) in ethyl acetate (5mL) was added platinum(IV) oxide (1.8 mg, 7.93 μmol). The reaction wasdegassed, purged with argon (3×), and charged with a H₂ balloonovernight. The mixture was filtered and washed with MeOH. The filtratewas concentrated. The residue was treated 1 mL HCl (4 N in dioxane) for1 h and then concentrated to yield the desired product (3.5 mg, 100%) asa brown solid (diastereomer mixture). MS(ESI) m/z: 387.2 (M+H)⁺.

Example 87. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-6-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt (diastereomer mixture): Example 87 was made in the same way asExample 2 by replacing 2M with 87C. ¹H NMR (500 MHz, MeOD) δ 8.75 (d,J=5.8 Hz, 1H), 8.28-8.00 (m, 2H), 7.93-7.74 (m, 2H), 7.67-7.41 (m, 3H),5.35 (d, J=5.3 Hz, 1H), 3.80 (s, 3H), 2.83 (br. s., 1H), 2.44 (d, J=1.0Hz, 3H), 2.23 (br. s., 1H), 2.09-1.85 (m, 1H), 1.81-1.42 (m, 3H), 1.26(d, J=18.1 Hz, 1H), 0.99 (d, J=7.0 Hz, 3H), 0.62-0.42 (m, 1H) ppm.MS(ESI) m/z: 624.2 (M+H)⁺. Analytical HPLC RT=5.79 min (Method A).

Example 88 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-13-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

88A.(S,E)-N-((4-Chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide:Angew. Chem. Int. Ed., 48:914-917 (2009). To a stirred suspension of(S)-2-methylpropane-2-sulfinamide (5 g, 41.3 mmol) and Cs₂CO₃ (20.16 g,61.9 mmol) in DCM (100 mL) was added a solution of4-chloropicolinaldehyde (5.84 g, 41.3 mmol) in DCM (50 mL) dropwise overa period of 10 min. The solution was then stirred for 2 h at rt. Thereaction mixture was diluted with EtOAc (50 mL) and washed with brine(20 mL×3). The organic layer was dried over MgSO₄ and concentrated togive the desired product (9.56 g, 95%) as brown thick oil. MS(ESI) m/z:246.9 (M+H)⁺.

88B.(S)—N-((1S,2R)-1-(4-Chloropyridin-2-yl)-2-methylbut-3-enyl)-2-methylpropane-2-sulfinamide:To a solution of 88A (1.7 g, 6.95 mmol) in THF (50 mL) at −78° C. wasadded 1-methyl-2-propenylmagnesium chloride (0.5 M in THF) (13.89 mL,6.95 mmol) dropwise over a period of 1 h. The resulting solution wasstirred at −78° C. for 0.5 h and at rt overnight. The reaction wascooled to 0° C. and quenched with saturated NH₄Cl. The mixture wasextracted with EtOAc (3×). The combined organic layer was concentratedand purified by silica gel chromatography to give the desired product(1.27 g, 61%) as a crude beige oil. ¹H NMR indicated a ˜4:1 mixture ofdiastereomers whereby the major diastereomer corresponds to the titlecompound. MS(ESI) m/z: 301.1 (M+H)⁺.

88C. tert-Butyl(1S,2R)-1-(4-chloropyridin-2-yl)-2-methylbut-3-enylcarbamate: To asolution of 88B (1.27 g, 4.22 mmol) in MeOH (20 mL) at 0° C. was addedHCl (5.28 mL, 21.11 mmol) (4 M in dioxane). The reaction was warmed tort and stirred for 1 h. The mixture was concentrated and added Et₂O. Theyellow suspension was filtered, washed Et₂O and dried. The above solidwas dissolved in DCM (20 mL) and Et₃N (2.354 mL, 16.89 mmol) and cooledto 0° C. BOC₂O (0.980 mL, 4.22 mmol) was added and the reaction wasstirred at rt for 2 h. The reaction was diluted with saturated NaHCO₃and extracted with DCM (2×). The combined organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography to give the desired product (1 g,80% yield) as a white solid. MS(ESI) m/z: 297.1 (M+H)⁺.

88D. tert-Butyl(1S,2R)-1-(4-(2-amino-4-nitrophenyl)pyridin-2-yl)-2-methylbut-3-enylcarbamate:To a 20 mL microwave vial was added 88C (0.25 g, 0.842 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitroaniline (0.253 g, 1.011mmol), potassium phosphate, tribasic (0.358 g, 1.685 mmol), water (0.076mL, 4.21 mmol) and DMSO (4.21 mL). The mixture was bubbled with N₂ for 5min and added PdCl₂(dppf)-CH₂Cl₂ adduct (0.069 g, 0.084 mmol). The vialwas sealed and heated at 90° C. for 3 h and then stirred at rt for 2 d.The mixture was partitioned between EtOAc and brine. The aqueous layerwas extracted with EtOAc. The combined organic layer was concentratedand purified by silica gel chromatography to yield the desired product(0.27 g, 80%) as a yellow foam. MS(ESI) m/z: 399.1 (M+H)⁺.

88E. tert-Butyl((1S,2R)-1-(4-(2,4-diaminophenyl)pyridin-2-yl)-2-methylbut-3-en-1-yl)carbamate:To a clear orange solution of 88D (0.27 g, 0.678 mmol) in methanol (6.78mL) was added zinc (0.443 g, 6.78 mmol) and NH₄Cl (0.362 g, 6.78 mmol).The resulting yellow-orange suspension turned clear after a few minutesand was stirred at rt for 1 h. The reaction was filtered and washed withMeOH. The filtrate was concentrated. The residue was diluted with EtOAcand washed with saturated aq. NaHCO₃, brine, dried over MgSO₄, filtered,and concentrated to give the desired product (0.25, 100%) as a brownishfoam. MS(ESI) m/z: 369.2 (M+H)⁺.

88F. tert-ButylN-[(1S)-1-(4-{2-amino-4-[(methoxycarbonyl)amino]phenyl}pyridin-2-yl)-2-methylbut-3-en-1-yl]carbamate:To a clear orange solution of 88E (0.25 g, 0.678 mmol) and pyridine(0.055 mL, 0.678 mmol) in DCM (6.78 ml) at −78° C. was added methylchlorocarbonate (0.047 mL, 0.611 mmol) dropwise. The reaction wasstirred at −78° C. for 1 h and quenched with saturated NH₄Cl. Thereaction was diluted with EtOAc and water. The aqueous layer wasextracted with EtOAc. The combined organic layer was washed with brine,dried over MgSO₄, filtered and concentrated to give the desired product(0.3 g, 100%) as a brown glass. MS(ESI) m/z: 427.1 (M+H)⁺.

88G. tert-ButylN-[(1S)-1-{4-[2-(but-3-enamido)-4-[(methoxycarbonyl)amino]phenyl]pyridin-2-yl}-2-methylbut-3-en-1-yl]carbamate:To a solution of 88F (100 mg, 0.234 mmol) and but-3-enoic acid (0.020mL, 0.234 mmol) in pyridine (1 mL) at 0° C. was added POCl₃ (0.044 mL,0.469 mmol). The resulting orange solution was stirred at 0° C. for 10min and diluted with DCM. The mixture was washed with aq. NaHCO₃, brine,and concentrated. The residue was purified by silica gel chromatographyto give the desired product (52 mg, 45%) as a beige foam. MS(ESI) m/z:495.1 (M+H)⁺.

88H. tert-ButylN-[(11E,14S)-5-[(methoxycarbonyl)amino]-13-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,11,15,17-heptaen-14-yl]carbamate:A solution of 88G (89 mg, 0.180 mmol) in toluene (20 mL) was bubbledwith N₂ for 10 min. Grubbs II (61.1 mg, 0.072 mmol) was added and thereaction mixture was heated at 160° C. under microwave conditions for 20min. The reaction was concentrated and purified by reverse phase HPLC toisolate the desired product (10 mg, 12%). MS(ESI) m/z: 467.1 (M+H)⁺.

88I. MethylN-[(14S)-14-amino-13-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,HCl salt: To a solution of 88H (10 mg, 0.021 mmol) in MeOH was addedplatinum(IV) oxide (9 mg, 0.040 mmol). The mixture was evacuated, purgedwith H₂ (3×), and then charged with 50 psi H₂ overnight. The mixture wasfiltered and the filtrate was concentrated. The residue was treated with1 mL HCl (4 N in dioxane) and stirred at rt for 1 h. The mixture wasconcentrated to yield the desired product (10 mg, 23%). MS(ESI) m/z:369.2 (M+H)⁺.

Example 88. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-13-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: To a solution of 88I (10 mg, 0.023 mmol), Intermediate 21(6.95 mg, 0.027 mmol), HOBT (5.20 mg, 0.034 mmol) and EDC (6.52 mg,0.034 mmol) in DMF (1 mL) was added DIEA (0.040 mL, 0.227 mmol). Theresulting solution was stirred at rt overnight. The reaction wasquenched with aq. NaHCO₃ and then extracted with DCM (2×30 mL). Thecombined organic layer was concentrated and purified by reverse phaseHPLC to yield the desired product (2.5 mg, 18%) as a white solid. ¹H NMR(400 MHz, MeOD) δ 8.61 (d, J=5.0 Hz, 1H), 7.81 (td, J=7.5, 1.5 Hz, 1H),7.65-7.32 (m, 7H), 5.48 (s, 1H), 5.04 (d, J=10.8 Hz, 1H), 3.76 (s, 3H),2.64-2.54 (m, 1H), 2.52-2.42 (m, 3H), 2.18-2.03 (m, 1H), 1.82 (d, J=11.3Hz, 3H), 1.43-1.26 (m, 3H), 1.21 (d, J=7.0 Hz, 2H), 1.07 (d, J=7.0 Hz,1H), 0.90 (d, J=6.8 Hz, 1H), 0.72 (br. s., 1H) ppm. MS(ESI) m/z: 606.2(M+H)⁺. Analytical HPLC RT=5.40 min (Method A).

Example 89N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,2 TFA salt

89A. tert-ButylN-[(10R,14S)-5-amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate:To the suspension of 2L (0.9 g, 1.921 mmol) in MeOH (29.6 ml) was added1 N NaOH (11.53 ml, 11.53 mmol). The reaction was stirred in a sealedtube at 75° C. overnight. The reaction was cooled to rt andconcentrated. The residue was partitioned between 15% IPA/CHCl₃ andwater. The organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated to give the desired product (0.79 g, 100%) asa brown solid. MS(ESI) m/z: 411.1 (M+H)⁺.

89B.(10R,14S)-5,14-Diamino-10-methyl-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one:89A (0.75 g, 1.827 mmol) was treated with HCl (4 M in 1,4-dioxane) (10mL, 40.0 mmol) and the reaction was stirred at rt for 1 h. The yellowsuspension was filtered, rinsed with hexane and dried to give thedesired product (0.87 g, 100%). MS(ESI) m/z: 311.1 (M+H)⁺.

Example 89.N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,2 TFA salt: A yellow solution of Intermediate 21 (0.229 g, 0.896 mmol),89B (0.45 g, 0.943 mmol), EDC (0.362 g, 1.887 mmol), HOBT (0.289 g,1.887 mmol), and Hunig's base (0.824 mL, 4.72 mmol) in DMF (6.29 mL) wasstirred at rt overnight. The reaction was quenched with water. Theresulting yellow suspension was filtered, dried and purified by reversephase HPLC to isolate the desired product (0.454 g, 62%) as a yellowfoam. ¹H NMR (500 MHz, MeOD) δ 8.62 (d, J=6.3 Hz, 1H), 8.22 (d, J=1.9Hz, 1H), 7.87 (dd, J=6.2, 1.8 Hz, 1H), 7.82 (ddd, J=8.3, 6.8, 1.7 Hz,1H), 7.56 (ddd, J=8.0, 6.5, 1.7 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H),7.48-7.44 (m, 1H), 6.80 (dd, J=8.5, 2.2 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H),5.35 (dd, J=11.3, 6.1 Hz, 1H), 2.83-2.75 (m, 1H), 2.43 (d, J=0.8 Hz,3H), 2.29-2.19 (m, 1H), 2.09-1.96 (m, 2H), 1.73-1.52 (m, 2H), 0.98 (d,J=6.9 Hz, 3H), 0.60-0.49 (m, 1H) ppm. MS(ESI) m/z: 548.1 (M+H)⁺.Analytical HPLC RT=3.99 min (Method A).

Example 89 (Alternative, 2 HCl salt): Example 89 (0.067 g, 0.086 mmol)was dissolved in 1.25 M HCl in MeOH (1 mL, 1.250 mmol) and thenconcentrated. The process was repeated one more time to give the desiredproduct (55 mg, 100%) as a yellow solid.

Example 90N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide,2 TFA salt

Example 90.N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide,2 TFA salt: Example 90 was made in the same way as Example 89 byreplacing Intermediate 21 with Intermediate 25. ¹H NMR (500 MHz, MeOD) δ8.58 (d, J=6.3 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J=1.9 Hz, 1H), 7.85 (dd,J=6.2, 1.8 Hz, 1H), 7.72 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.49 (d, J=8.5Hz, 1H), 7.46 (ddd, J=8.0, 6.5, 1.7 Hz, 1H), 7.41-7.36 (m, 1H), 6.77(dd, J=8.5, 2.2 Hz, 1H), 6.58 (d, J=2.2 Hz, 1H), 5.22 (dd, J=11.4, 5.9Hz, 1H), 2.81-2.74 (m, 1H), 2.35 (d, J=1.1 Hz, 3H), 2.25-2.16 (m, 1H),2.04-1.95 (m, 2H), 1.71-1.61 (m, 1H), 1.61-1.50 (m, 1H), 0.98 (d, J=6.9Hz, 3H), 0.61-0.51 (m, 1H) ppm. MS(ESI) m/z: 547.3 (M+H)⁺. AnalyticalHPLC RT=4.57 min (Method D).

Example 91N-[(10S,14S)-5-Amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide,2 TFA

Example 91.N-[(10S,14S)-5-Amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide,2 TFA: Example 91 was made in the same way as Example 90 by using theother isomer. ¹H NMR (500 MHz, MeOD) δ 8.58 (d, J=6.1 Hz, 1H), 8.29 (s,1H), 8.09 (s, 1H), 7.83 (dd, J=6.2, 1.8 Hz, 1H), 7.71 (ddd, J=8.2, 6.7,1.7 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.45 (ddd, J=8.0, 6.5, 1.7 Hz, 1H),7.40-7.35 (m, 1H), 6.79 (dd, J=8.5, 2.2 Hz, 1H), 6.60 (d, J=2.2 Hz, 1H),5.13 (dd, J=11.3, 5.2 Hz, 1H), 2.46-2.38 (m, 1H), 2.36 (d, J=0.8 Hz,3H), 2.23-2.14 (m, 1H), 2.07-1.98 (m, 1H), 1.80-1.70 (m, 1H), 1.66-1.56(m, 1H), 1.31-1.22 (m, 4H), 1.06-0.95 (m, 1H) ppm. MS(ESI) m/z: 547.3(M+H)⁺. Analytical HPLC RT=4.45 min (Method D).

Example 92N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide,TFA salt

Example 92.N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide,TFA salt: Example 92 was made in the same way as Example 89 by replacing4-chloropicolinaldehyde with 2-bromoisonicotinaldehyde in step 2A andreplacing Intermediate 21 with Intermediate 25. ¹H NMR (500 MHz,acetonitrile-d₃) δ 8.68 (d, J=6.33 Hz, 1H), 8.29 (s, 1H), 8.14 (s, 1H),8.12 (d, J=1.65 Hz, 1H), 7.65-7.73 (m, 1H), 7.51 (s, 1H), 7.49 (s, 1H),7.45 (ddd, J=1.79, 6.60, 8.12 Hz, 1H), 7.34-7.40 (m, 1H), 7.31 (d,J=5.78 Hz, 1H), 6.72 (dd, J=2.20, 8.53 Hz, 1H), 6.53 (d, J=2.20 Hz, 1H),5.16 (td, J=5.95, 11.49 Hz, 1H), 2.61-2.72 (m, 1H), 2.35 (d, J=1.10 Hz,3H), 2.07-2.15 (m, 1H), 1.93-1.98 (m, 2H), 1.88-1.93 (m, 1H), 1.42-1.62(m, 2H), 0.93 (d, J=6.88 Hz, 3H), 0.55-0.65 (m, 1H) ppm. MS(ESI) m/z:547.5 (M+H)⁺. Analytical HPLC RT=5.43 min (Method A).

Example 93N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxamide,TFA salt

Example 93.N-[(10R,14S)-5-Amino-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxamide,TFA salt: Example 93 was made in the same way as Example 92 by replacingIntermediate 25 with Intermediate 24. ¹H NMR (500 MHz, MeOD) δ 8.61 (d,J=6.3 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.86 (dd, J=6.3, 1.9 Hz, 1H),7.83 (s, 1H), 7.73 (ddd, J=8.3, 6.7, 1.8 Hz, 1H), 7.50 (d, J=8.3 Hz,1H), 7.47-7.43 (m, 1H), 7.42-7.37 (m, 1H), 6.78 (dd, J=8.5, 2.2 Hz, 1H),6.59 (d, J=2.2 Hz, 1H), 5.28 (dd, J=11.3, 6.1 Hz, 1H), 2.82-2.75 (m,1H), 2.32 (br. s, 3H), 2.27-2.17 (m, 1H), 2.04-1.95 (m, 2H), 1.73-1.63(m, 1H), 1.63-1.52 (m, 1H), 0.98 (d, J=7.2 Hz, 3H), 0.58-0.48 (m, 1H)ppm. MS(ESI) m/z: 547.3 (M+H)⁺. Analytical HPLC RT=4.66 min (Method D).

Example 941-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-[(methylcarbamoyl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 94.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-[(methylcarbamoyl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: To a solution of Example 89 (0.02 g, 0.026 mmol) in DCM (1 mL)and acetonitrile (1 mL) was added sodium bicarbonate (6.49 mg, 0.077mmol). The mixture was cooled to 0° C. under argon, and then addedphosgene solution (20% in toluene) (0.041 mL, 0.077 mmol). The mixturewas stirred at 0° C. for 30 min and concentrated. The residue wasdissolved in acetonitrile (1 mL) and DCM (1 mL) under argon and cooledto 0° C. Methanamine, HCl salt (5.22 mg, 0.077 mmol) and TEA (7.18 μL,0.052 mmol) were added. The resulting cloudy mixture was stirred at 0°C. for 30 min, and then at rt overnight. The reaction was concentratedand the residue was purified by reverse phase HPLC to yield the desiredproduct (8 mg, 43%) as a yellow solid. ¹H NMR (500 MHz, MeOD) δ 8.73 (d,J=6.3 Hz, 1H), 8.26 (d, J=1.7 Hz, 1H), 7.92 (dd, J=6.2, 1.8 Hz, 1H),7.82 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.58-7.53(m, 2H), 7.49-7.41 (m, 2H), 5.37 (dd, J=11.3, 6.1 Hz, 1H), 2.83-2.75 (m,4H), 2.43 (d, J=0.8 Hz, 3H), 2.30-2.21 (m, 1H), 2.08-1.92 (m, 2H),1.70-1.50 (m, 2H), 0.97 (d, J=7.2 Hz, 3H), 0.57-0.45 (m, 1H) ppm.MS(ESI) m/z: 605.1 (M+H)⁺. Analytical HPLC RT=5.50 min (Method A).

Example 95 Propan-2-ylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 95. Propan-2-ylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: To the solution of Example 89 (0.025 g, 0.032 mmol), pyridine(0.013 mL, 0.161 mmol) in DCM (1 mL) at 0° C. was added isopropylcarbonochloridate (1 M in toluene) (0.097 mL, 0.097 mmol). The reactionwas stirred at rt for 1 h and quenched with MeOH. The mixture wasconcentrated and purified by reverse phase HPLC to yield the desiredproduct (0.015 g, 61%) as a white solid. ¹H NMR (500 MHz, MeOD) δ 8.75(d, J=6.1 Hz, 1H), 8.27 (d, J=1.4 Hz, 1H), 7.94 (dd, J=6.1, 1.9 Hz, 1H),7.81 (ddd, J=8.2, 6.8, 1.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.59-7.50(m, 3H), 7.48-7.43 (m, 1H), 5.37 (dd, J=11.3, 6.1 Hz, 1H), 4.99 (spt,J=6.2 Hz, 1H), 2.82-2.75 (m, 1H), 2.42 (d, J=0.8 Hz, 3H), 2.31-2.21 (m,1H), 2.10-1.92 (m, 2H), 1.70-1.51 (m, 2H), 1.32 (d, J=6.3 Hz, 6H), 0.97(d, J=6.9 Hz, 3H), 0.57-0.45 (m, 1H) ppm. MS(ESI) m/z: 634.2 (M+H)⁺.Analytical HPLC RT=6.86 min (Method A).

The following Examples in Table 8 were made in the same way as shown inExample 95. Carbonochloridates can be either from commercial source orgenerated by corresponding alcohol with various reagents such asphosgene, triphosgene. Carbonochloridates can also be replaced withactivated alcohols by treating alcohols with 4-nitrophenylcarbonochloridate.

TABLE 8 RT, min Example # Stereochemistry X R M + H Method A  96Homochiral N

650.3 6.18  97 Homochiral N

676.2 6.37  98 Homochiral N

648.4 5.92  99 Homochiral N

754.4 8.21 100 Homochiral N

673.2 6.15 101 Diastereomer mixture N

662.2 6.10 102 Diastereomer mixture N

676.2 6.41 103 Homochiral N

673.1 6.07 104 Homochiral N

673.1 6.11 105 Diastereomer mixture N

704.2 7.22 106 Homochiral from cis diol N

676.2 6.15 107 Homochiral from cis diol N

676.2 6.15 108 Homochiral from trans diol N

676.2 4.09 109 Homochiral from trans diol N

676.3 4.10 110 Diastereomer mixture N

690.3 4.07 111 Homochiral N

673.2 6.46 112 Homochiral N

673.1 6.48 113 Homochiral N

673.3 6.49 114 Homochiral N

664.2 4.09 115 Homochiral N

664.2 5.94 116 Homochiral N

678.2 7.18 117 Diastereomer mixture N

704.2 7.70 118 Homochiral N

664.2 6.32 119 Homochiral CH

649.3 6.11 120 Homochiral CH

619.3 6.52 121 Homochiral CH

635.3 5.92 122 Homochiral CH

675.3 6.11 123 Diastereomer mixture CH

675.3 6.10 124 Homochiral CH

649.2 5.41 125 Homochiral CH

691.4 6.54 126 Diastereomer mixture CH

661.2 5.80 127 Homochiral CH

661.3 5.73 128 Homochiral CH

673.3 8.07 129 Homochiral CH

689.3 6.20 130 Homochiral CH

689.3 6.20 131 Homochiral CH

682.2 5.46 132 Homochiral CH

663.2 6.57 133 Homochiral CH

671.2 7.05 134 Homochiral CH

675.2 6.05

Example 1351-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-[(dimethylcarbamoyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 135.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-[(dimethylcarbamoyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 135 was made the same way as with Example 94 byreplacing methanamine, HCl salt with dimethylamine, HCl salt. ¹H NMR(500 MHz, MeOD) δ 8.74 (d, J=6.1 Hz, 1H), 8.27 (d, J=1.7 Hz, 1H), 7.94(dd, J=6.2, 1.8 Hz, 1H), 7.82 (ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.64 (d,J=8.5 Hz, 1H), 7.58-7.51 (m, 3H), 7.48-7.44 (m, 1H), 5.37 (dd, J=11.4,6.2 Hz, 1H), 3.06 (s, 6H), 2.83-2.75 (m, 1H), 2.43 (d, J=1.1 Hz, 3H),2.26 (m, 1H), 2.10-1.92 (m, 2H), 1.70-1.51 (m, 2H), 0.97 (d, J=6.9 Hz,3H), 0.58-0.46 (m, 1H) ppm. MS(ESI) m/z: 619.1 (M+H)⁺. Analytical HPLCRT=5.64 min (Method A).

Example 1361-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-methanesulfonamido-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 136.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-methanesulfonamido-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: To the solution of Example 89 (Alternative, HCl salt) (0.012g, 0.019 mmol) in pyridine (0.5 mL, 6.18 mmol) and DCM (1 mL) at 0° C.was added methanesulfonyl chloride (2.3 μL, 0.029 mmol). The reactionwas stirred at 0° C. for 1 h and concentrated. The residue was purifiedby reverse phase HPLC to yield the desired product (10 mg, 69% yield) asa white solid. ¹H NMR (500 MHz, MeOD) δ 8.74 (d, J=5.8 Hz, 1H), 8.07 (d,J=1.4 Hz, 1H), 7.84-7.76 (m, 2H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (ddd,J=8.0, 6.5, 1.7 Hz, 1H), 7.48-7.43 (m, 1H), 7.32 (dd, J=8.4, 2.3 Hz,1H), 7.23 (d, J=2.5 Hz, 1H), 5.34 (dd, J=11.1, 5.9 Hz, 1H), 3.08 (s,3H), 2.79-2.72 (m, 1H), 2.44 (d, J=0.8 Hz, 3H), 2.27-2.17 (m, 1H),2.02-1.89 (m, 2H), 1.64-1.47 (m, 2H), 0.96 (d, J=6.9 Hz, 3H), 0.54-0.43(m, 1H) ppm. MS(ESI) m/z: 626.1 (M+H)⁺. Analytical HPLC RT=6.02 min(Method A).

Example 1371-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(trifluoroacetamido)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 137.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(trifluoroacetamido)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 137 was made in the same way as Example 136 by usingExample 89. ¹H NMR (500 MHz, MeOD) δ 8.74 (d, J=5.8 Hz, 1H), 8.02 (s,1H), 7.82 (ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.78-7.69 (m, 4H), 7.56 (ddd,J=8.1, 6.5, 1.7 Hz, 1H), 7.48-7.43 (m, 1H), 5.34 (dd, J=11.1, 5.9 Hz,1H), 2.79-2.72 (m, 1H), 2.44 (d, J=0.8 Hz, 3H), 2.25-2.16 (m, 1H),2.00-1.89 (m, 2H), 1.62-1.45 (m, 2H), 0.96 (d, J=6.9 Hz, 3H), 0.54-0.43(m, 1H) ppm. MS(ESI) m/z: 644.2 (M+H)⁺. Analytical HPLC RT=7.07 min(Method A).

Example 1381-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-acetamido-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 138.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-acetamido-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 138 was made in the same way as Example 136 byreplacing methanesulfonyl chloride with acetyl chloride. ¹H NMR (500MHz, MeOD) δ 8.75 (d, J=6.1 Hz, 1H), 8.22 (d, J=1.4 Hz, 1H), 7.91 (dd,J=6.1, 1.7 Hz, 1H), 7.82 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.76 (d, J=1.9Hz, 1H), 7.69-7.65 (m, 1H), 7.60 (dd, J=8.5, 2.2 Hz, 1H), 7.56 (ddd,J=8.1, 6.5, 1.7 Hz, 1H), 7.46 (td, J=8.2, 1.5 Hz, 1H), 5.36 (dd, J=11.3,6.1 Hz, 1H), 2.81-2.74 (m, 1H), 2.43 (d, J=1.1 Hz, 3H), 2.31-2.20 (m,1H), 2.17 (s, 3H), 2.07-1.90 (m, 2H), 1.67-1.50 (m, 2H), 0.97 (d, J=7.2Hz, 3H), 0.56-0.45 (m, 1H) ppm. MS(ESI) m/z: 590.2 (M+H)⁺. AnalyticalHPLC RT=5.63 min (Method A).

Example 139 FluoromethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

139A. Fluoromethyl carbonofluoridate: A mixture of chloromethylcarbonochloridate (0.16 g, 1.241 mmol), potassium fluoride (0.29 g, 4.99mmol), and 18-crown-6 (0.1 g, 0.378 mmol) in acetonitrile (2.5 mL) in asealed tube was stirred at rt overnight. The mixture was used in thenext step without further purification as a 0.5 M solution.

Example 139. FluoromethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 139 was made in the same way as Example 136 byreplacing methanesulfonyl chloride with 139A. ¹H NMR (500 MHz, MeOD) δ8.77 (d, J=6.3 Hz, 1H), 8.28 (d, J=1.7 Hz, 1H), 7.95 (dd, J=6.1, 1.9 Hz,1H), 7.82 (ddd, J=8.3, 6.9, 1.7 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.62(s, 1H), 7.59-7.54 (m, 2H), 7.46 (td, J=8.1, 1.4 Hz, 1H), 5.86-5.83 (m,1H), 5.76-5.72 (m, 1H), 5.37 (dd, J=11.3, 6.1 Hz, 1H), 2.83-2.75 (m,1H), 2.42 (d, J=0.8 Hz, 3H), 2.30-2.21 (m, 1H), 2.10-1.91 (m, 2H),1.70-1.51 (m, 2H), 0.97 (d, J=6.9 Hz, 3H), 0.54-0.43 (m, 1H) ppm.MS(ESI) m/z: 624.2 (M+H)⁺. Analytical HPLC RT=6.44 min (Method A).

Example 140 FluoromethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 140. FluoromethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 140 was made in the same way as Example 139 byreplacing Example 89 with Example 92. ¹H NMR (500 MHz, acetonitrile-d₃)δ 8.62 (d, J=5.78 Hz, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H),7.84 (s, 1H), 7.66 (d, J=8.53 Hz, 1H), 7.57 (ddd, J=1.79, 6.74, 8.25 Hz,1H), 7.38-7.41 (m, 2H), 7.30-7.35 (m, 2H), 7.21-7.28 (m, 1H), 7.14 (d,J=6.05 Hz, 1H), 5.00 (td, J=5.88, 11.62 Hz, 1H), 4.58-4.61 (m, 1H),4.48-4.51 (m, 1H), 4.30-4.33 (m, 1H), 4.25-4.28 (m, 1H), 2.55 (dt,J=2.75, 6.46 Hz, 1H), 2.24 (d, J=1.10 Hz, 3H), 1.91-2.01 (m, 2H),1.68-1.80 (m, 3H), 1.41 (dt, J=6.33, 12.79 Hz, 1H), 1.27-1.36 (m, 1H),0.82 (d, J=6.88 Hz, 2H), 0.46-0.59 (m, 1H) ppm. MS(ESI) m/z: 637.6(M+H)⁺. Analytical HPLC RT=6.09 min (Method A).

Example 1411-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-(2-methoxyacetamido)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 141.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-(2-methoxyacetamido)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 141 was made in the same way as Example 136 byreplacing methanesulfonyl chloride with 2-methoxyacetyl chloride. ¹H NMR(500 MHz, acetonitrile-d₃) δ 8.63-8.69 (m, 1H), 8.60 (d, J=5.78 Hz, 1H),8.36 (d, J=7.15 Hz, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.67 (ddd, J=1.65,6.88, 8.25 Hz, 1H), 7.64 (s, 1H), 7.46-7.53 (m, 3H), 7.38-7.44 (m, 1H),7.29-7.35 (m, 1H), 5.24 (td, J=6.53, 10.87 Hz, 1H), 3.91 (s, 3H), 3.38(s, 3H), 2.51-2.58 (m, 2H), 2.33 (s 3H), 1.97-2.09 (m, 2H), 1.30-1.44(m, 2H), 0.81 (d, J=6.88 Hz, 3H), 0.30-0.35 (m, 1H) ppm. MS(ESI) m/z:620.6 (M+H)⁺. Analytical HPLC RT=6.06 min (Method A).

Example 1421-(3-Chloro-2-fluorophenyl)-N-[(10S,14S)-5-(2-methoxyacetamido)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 142.1-(3-Chloro-2-fluorophenyl)-N-[(10S,14S)-5-(2-methoxyacetamido)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 142 was made in the same way as Example 141 by usingthe other isomer. ¹H NMR (500 MHz, acetonitrile-d₃) δ 8.66 (s, 1H), 8.61(d, J=5.50 Hz, 1H), 8.35 (d, J=6.60 Hz, 1H), 7.93 (s, 1H), 7.65-7.69 (m,2H), 7.64 (d, J=2.20 Hz, 1H), 7.56 (dd, J=2.20, 8.53 Hz, 1H), 7.46-7.50(m, 2H), 7.41 (ddd, J=1.65, 6.53, 8.05 Hz, 1H), 7.33 (dt, J=1.51, 8.18Hz, 1H), 5.18 (td, J=5.61, 11.62 Hz, 1H), 3.90 (s, 3H), 3.36 (s, 3H),2.34 (d, J=1.10 Hz, 3H), 2.02-2.17 (m, 2H), 1.74-1.81 (m, 1H), 1.56-1.67(m, 1H), 1.25-1.37 (m, 2H), 1.09 (d, J=7.15 Hz, 3H), 0.74-0.87 (m, 1H)ppm. MS(ESI) m/z: 620.6 (M+H)⁺. Analytical HPLC RT=6.11 min (Method A).

Example 1431-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(2-oxopropanamido)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 143.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(2-oxopropanamido)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 143 was made in the same way as Example 136 byreplacing methanesulfonyl chloride with 2-oxopropanoyl chloride. ¹H NMR(500 MHz, MeOD) δ 8.72 (d, J=5.2 Hz, 1H), 7.91 (td, J=7.6, 1.5 Hz, 1H),7.85 (s, 1H), 7.82-7.77 (m, 2H), 7.72-7.67 (m, 1H), 7.64-7.57 (m, 2H),7.51 (td, J=8.3, 1.4 Hz, 1H), 5.25 (dd, J=10.6, 5.6 Hz, 1H), 2.71-2.62(m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.05-1.96 (m, 1H), 1.89-1.78 (m,2H), 1.47-1.24 (m, 2H), 0.82 (d, J=6.9 Hz, 3H), 0.31-0.20 (m, 1H) ppm.MS(ESI) m/z: 618.1 (M+H)⁺. Analytical HPLC RT=6.34 min (Method A).

Example 1441-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-(2-hydroxypropanamido)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 144.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-(2-hydroxypropanamido)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: To the solution of Example 143 (0.019 g, 0.026 mmol) in MeOH(1 mL) was added sodium borohydride (2 mg, 0.052 mmol). The reactionmixture was stirred at rt for 1 h and concentrated. The residue waspurified by reverse phase HPLC to yield the desired product (8 mg, 40%)as a yellow solid. ¹H NMR (500 MHz, MeOD) δ 8.75 (d, J=5.8 Hz, 1H), 8.17(s, 1H), 7.86 (dd, J=5.9, 1.8 Hz, 1H), 7.84-7.79 (m, 2H), 7.73-7.65 (m,2H), 7.56 (ddd, J=8.1, 6.5, 1.7 Hz, 1H), 7.46 (td, J=8.1, 1.4 Hz, 1H),5.36 (dd, J=11.1, 5.9 Hz, 1H), 4.29 (q, J=6.9 Hz, 1H), 2.81-2.74 (m,1H), 2.43 (d, J=0.8 Hz, 3H), 2.28-2.19 (m, 1H), 2.05-1.91 (m, 2H),1.66-1.49 (m, 2H), 1.45 (d, J=6.9 Hz, 3H), 0.97 (d, J=7.2 Hz, 3H),0.56-0.44 (m, 1H) ppm. MS(ESI) m/z: 620.2 (M+H)⁺. Analytical HPLCRT=5.62 min (Method A).

Example 145 2-HydroxypropylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

145A. 2-OxopropylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate:To a solution of Example 89 (0.02 g, 0.032 mmol) in DCM (1 mL) andacetonitrile (1 mL) was added sodium bicarbonate (8.12 mg, 0.097 mmol).The mixture was cooled to 0° C. under argon, and then added phosgenesolution (20% in toluene) (0.051 mL, 0.097 mmol). After another 2 h, thereaction was concentrated. The residue was dissolved in acetonitrile (1mL) and DCM (1 mL) and cooled to 0° C. under argon.1-Hydroxypropan-2-one (7.2 mg, 0.097 mmol) and TEA (9 μL, 0.064 mmol)were added and the resulting cloudy mixture was stirred at 0° C. for 30min, then at rt overnight. The reaction was concentrated and purified byreverse phase HPLC to isolate the desired product as a yellow solid (11mg, 18%). MS(ESI) m/z: 648.2 (M+H)⁺.

Example 145. 2-HydroxypropylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: To the solution of 145A (0.011 g, 5.77 μmol) in MeOH (1 mL)was added NaBH₄ (0.655 mg, 0.017 mmol). The reaction was stirred at rtfor 1 h and concentrated. The residue was purified by reverse phase HPLCto yield the desired product as a yellow solid (2 mg, 44% yield). ¹H NMR(500 MHz, MeOD) δ 8.71 (d, J=5.8 Hz, 1H), 8.05 (s, 1H), 7.82 (ddd,J=8.3, 6.8, 1.7 Hz, 1H), 7.75 (dd, J=5.8, 1.7 Hz, 1H), 7.61 (d, J=8.5Hz, 1H), 7.58-7.54 (m, 2H), 7.51 (dt, J=8.5, 2.1 Hz, 1H), 7.46 (td,J=8.2, 1.5 Hz, 1H), 5.34 (dd, J=11.3, 5.8 Hz, 1H), 4.12-3.99 (m, 3H),2.80-2.72 (m, 1H), 2.44 (d, J=0.8 Hz, 3H), 2.25-2.16 (m, 1H), 2.01-1.91(m, 2H), 1.65-1.46 (m, 2H), 1.23 (d, J=6.3 Hz, 3H), 0.97 (d, J=7.2 Hz,3H), 0.54-0.43 (m, 1H) ppm. MS(ESI) m/z: 650.2 (M+H)⁺. Analytical HPLCRT=5.77 min (Method A).

Example 146 tert-Butyl2-{[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamoyl}acetate,TFA salt

Example 146. tert-Butyl2-{[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamoyl}acetate,TFA salt: To a solution of Example 89 (0.02 g, 0.026 mmol) in DMF (1 mL)was added 3-(tert-butoxy)-3-oxopropanoic acid (0.012 g, 0.077 mmol), EDC(9.88 mg, 0.052 mmol), HOBT (7.89 mg, 0.052 mmol), and DIPEA (0.023 mL,0.129 mmol). The reaction was stirred at rt overnight and at 55° C. for2 h. The mixture was cooled to rt and concentrated. The residue waspurified by reverse phase to yield the desired product (12 mg, 57%) as awhite solid. ¹H NMR (500 MHz, MeOD) δ 8.76 (d, J=6.1 Hz, 1H), 8.25 (d,J=1.7 Hz, 1H), 7.93 (dd, J=6.1, 1.9 Hz, 1H), 7.81 (ddd, J=8.3, 6.8, 1.7Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.62 (dd,J=8.4, 2.1 Hz, 1H), 7.56 (ddd, J=8.1, 6.5, 1.7 Hz, 1H), 7.46 (td, J=8.1,1.4 Hz, 1H), 5.37 (dd, J=11.3, 6.1 Hz, 1H), 3.43 (s, 2H), 2.82-2.74 (m,1H), 2.43 (d, J=0.8 Hz, 3H), 2.30-2.20 (m, 1H), 2.08-1.90 (m, 2H),1.68-1.43 (m, 11H), 0.97 (d, J=6.9 Hz, 3H), 0.56-0.45 (m, 1H) ppm.MS(ESI) m/z: 690.3 (M+H)⁺. Analytical HPLC RT=7.03 min (Method A).

Example 1471-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-[(E)-2-cyano-1-methylcarbamimidamido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

147A.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-{[(1Z)-(cyanoimino)(phenoxy)methyl]amino}-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide:A mixture of Example 89 (Alternative, HCl salt) (10 mg, 0.016 mmol),pyridine (10.42 μl, 0.129 mmol) and diphenyl cyanocarbonimidate (7.67mg, 0.032 mmol) in 2-propanol (0.15 mL) was stirred in a pressure-testedvial at room temperature for 2 h. The reaction mixture was concentratedto give the product (11 mg, 99%) as an oily solid. MS(ESI) m/z: 692.7(M+H)⁺.

Example 147.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-[(E)-2-cyano-1-methylcarbamimidamido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: A mixture of 147A (11 mg, 0.016 mmol) and monomethylamine(0.795 mL, 1.589 mmol) in 2-propanol (0.2 mL) was stirred in apressure-tested vial at room temperature for 1 h. Monomethylamine (0.795mL, 1.589 mmol) was added again and the reaction was stirred at rt foranother hour. The reaction was concentrated and purified by reversephase HPLC to yield the desired product (6.2 mg, 95%) as a white solid.¹H NMR (500 MHz, acetonitrile-d₃) δ 8.62 (d, J=5.78 Hz, 1H), 8.39 (d,J=6.88 Hz, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.67 (ddd, J=1.51, 6.88,8.12 Hz, 1H), 7.56 (dd, J=1.38, 5.78 Hz, 1H), 7.51 (d, J=8.53 Hz, 1H),7.46 (br. s., 1H), 7.42 (ddd, J=1.65, 6.53, 8.05 Hz, 1H), 7.33 (dt,J=1.38, 8.12 Hz, 1H), 7.28 (dd, J=1.79, 8.39 Hz, 1H), 7.23 (br. s., 1H),5.96 (d, J=3.58 Hz, 1H), 5.26 (td, J=6.57, 11.07 Hz, 1H), 2.80 (d,J=4.68 Hz, 3H), 2.52-2.60 (m, 2H), 2.33 (s, 2H), 2.01-2.09 (m, 2H),1.90-1.99 (m, 2H), 1.77 (t, J=12.10 Hz, 1H), 1.33-1.46 (m, 2H), 0.81 (d,J=6.88 Hz, 3H), 0.24-0.36 (m, 1H) ppm. MS(ESI) m/z: 629.6 (M+H)⁺.Analytical HPLC RT=5.92 min (Method A).

Example 1481-(3-Chloro-2-fluorophenyl)-N-[(10S,14S)-5-[(E)-2-cyano-1-methylcarbamimidamido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 148.1-(3-Chloro-2-fluorophenyl)-N-[(10S,14S)-5-[(E)-2-cyano-1-methylcarbamimidamido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 148 was made in the same way as Example 147 by usingthe other isomer. ¹H NMR (500 MHz, acetonitrile-d₃) δ 8.62 (d, J=5.50Hz, 1H), 8.33 (d, J=6.88 Hz, 1H), 7.88 (s, 1H), 7.64-7.70 (m, 1H), 7.61(s, 1H), 7.50 (d, J=8.25 Hz, 1H), 7.39-7.46 (m, 2H), 7.30-7.36 (m, 2H),7.26 (br. s., 1H), 5.90 (br. s., 1H), 5.13-5.20 (m, 1H), 2.80 (d, J=4.95Hz, 3H), 2.42 (d, J=6.05 Hz, 1H), 2.35 (d, J=0.55 Hz, 3H), 2.03-2.18 (m,2H), 1.67-1.78 (m, 2H), 1.66-1.60 (m, 1H), 1.25-1.35 (m, 4H), 1.08 (d,J=7.15 Hz, 3H), 0.88-83 (m, 1H) ppm. MS(ESI) m/z: 629.6 (M+H)⁺.Analytical HPLC RT=5.90 min (Method A).

Example 1491-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-{[6-(methoxymethyl)pyrimidin-4-yl]amino}-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 149.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-{[6-(methoxymethyl)pyrimidin-4-yl]amino}-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: The solution of Example 89 (Alternative, HCl salt) (0.01 g,0.016 mmol), 4-chloro-6-(methoxymethyl)pyrimidine (7.66 mg, 0.048 mmol),and DIPEA (0.014 mL, 0.081 mmol) in IPA (0.5 mL) was heated at 150° C.for 30 min under microwave conditions. The reaction was cooled to rt andconcentrated. The residue was purified by reverse phase to yield thedesired product (5 mg, 33%) as a yellow solid. ¹H NMR (500 MHz, MeOD) δ8.80 (d, J=0.8 Hz, 1H), 8.76 (d, J=5.8 Hz, 1H), 8.06 (d, J=1.1 Hz, 1H),7.84-7.73 (m, 5H), 7.56 (ddd, J=8.0, 6.5, 1.7 Hz, 1H), 7.46 (td, J=8.1,1.4 Hz, 1H), 7.04 (d, J=0.8 Hz, 1H), 5.35 (dd, J=11.1, 5.9 Hz, 1H), 4.58(d, J=0.6 Hz, 2H), 3.53 (s, 3H), 2.80-2.73 (m, 1H), 2.44 (d, J=0.8 Hz,3H), 2.26-2.17 (m, 1H), 2.02-1.90 (m, 2H), 1.64-1.47 (m, 2H), 0.97 (d,J=6.9 Hz, 3H), 0.55-0.45 (m, 1H) ppm. MS(ESI) m/z: 670.3 (M+H)⁺.Analytical HPLC RT=4.94 min (Method A).

Example 1501-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-[(E)-[(dimethylamino)methylidene]amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 150.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-[(E)-[(dimethylamino)methylidene]amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: The solution of Example 89 (Alternative, HCl salt) (0.01 g,0.016 mmol), ethyl 2-bromopropanoate (4.37 mg, 0.024 mmol), KI (0.802mg, 4.83 μmol), and K₂CO₃ (6.68 mg, 0.048 mmol) in DMF (0.5 mL) wasstirred at 120°C. for 5 h. The reaction was cooled to rt and purified byreverse phase HPLC to isolate the product (3.5 mg, 26%) as a yellowsolid. ¹H NMR (500 MHz, MeOD) δ 8.80-8.70 (m, 2H), 8.00 (br. s., 1H),7.85-7.72 (m, 3H), 7.60-7.50 (m, 2H), 7.49-7.43 (m, 1H), 7.35 (d, J=2.5Hz, 1H), 5.33 (dd, J=10.7, 5.8 Hz, 1H), 3.48 (s, 3H), 3.34 (s, 3H),2.78-2.71 (m, 1H), 2.44 (d, J=0.8 Hz, 3H), 2.26-2.16 (m, 1H), 2.01-1.86(m, 2H), 1.62-1.44 (m, 2H), 0.97 (d, J=7.2 Hz, 3H), 0.60-0.47 (m, 1H)ppm. MS(ESI) m/z: 603.2 (M+H)⁺. Analytical HPLC RT=3.93 min (Method A).

The following Examples in Table 9 were synthesized using methods similaras those described in Example 149.

TABLE 9 Example Stereo- M + RT, min # chemistry R H Method A 151Homochiral

626.2 5.83 152 Homochiral

626.2 6.08 153 Homochiral Early eluting diastereomer

648.1 6.58 154 Homochiral Late eluting diastereomer

648.2 6.65 155 Homochiral

606.1 4.00

Example 156 Ethyl2-{[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]amino}acetate,TFA salt

Example 156. Ethyl2-{[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]amino}acetate,TFA salt: To the solution of Example 89 (Alternative, HCl salt) (0.013g, 0.021 mmol) and ethyl 2-oxoacetate (6.23 μl, 0.031 mmol) in MeOH (0.5mL) was added acetic acid (1.2 μL, 0.021 mmol), followed by sodiumcyanoborohydride (1.3 mg, 0.021 mmol). The reaction was stirred at rtfor 2 h and concentrated. The residue was purified by reverse phase HPLCto yield the desired product (11 mg, 59%) as a yellow solid. ¹H NMR (500MHz, MeOD) δ 8.63 (d, J=6.3 Hz, 1H), 8.24 (d, J=1.9 Hz, 1H), 7.88 (dd,J=6.2, 1.8 Hz, 1H), 7.82 (ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.58-7.52 (m,2H), 7.46 (td, J=8.1, 1.4 Hz, 1H), 6.72 (dd, J=8.7, 2.3 Hz, 1H), 6.51(d, J=2.5 Hz, 1H), 5.36 (dd, J=11.6, 6.1 Hz, 1H), 4.22 (q, J=7.0 Hz,2H), 4.02 (s, 2H), 2.84-2.75 (m, 1H), 2.43 (d, J=0.8 Hz, 3H), 2.30-2.19(m, 1H), 2.09-1.95 (m, 2H), 1.74-1.52 (m, 2H), 1.28 (t, J=7.2 Hz, 3H),0.98 (d, J=6.9 Hz, 3H), 0.59-0.47 (m, 1H) ppm. MS(ESI) m/z: 634.2(M+H)⁺. Analytical HPLC RT=6.31 min (Method A).

Example 157 Methyl(10R,14S)-5-amino-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylate,2 TFA salt

157A. tert-ButylN-[(10R,14S)-5-amino-4-iodo-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate:To a solution of Example 89A (0.05 g, 0.122 mmol) in MeOH (2.5 mL) at 0°C. was added iodine monochloride (0.030 g, 0.183 mmol) in DCM (1.0 mL).The reaction was stirred at rt for 2 h and concentrated. The residue wasre-dissolved in EtOAc, washed with saturated NaHCO₃, brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel chromatography to yield the desired product (0.061 g, 93%) as ayellow solid. MS(ESI) m/z: 537.2 (M+H)⁺.

157B. Methyl(10R,14S)-5-amino-14-{[(tert-butoxy)carbonyl]amino}-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylate:The mixture of Pd(OAc)₂ (0.8 mg, 3.73 μmol), DPPF (2 mg, 3.73 μmol),K₂CO₃ (0.015 g, 0.112 mmol), TEA (5.2 μL, 0.037 mmol), and 157A (0.02 g,0.037 mmol) in acetonitrile (2 mL) and MeOH (1 mL) was vacuumed andbackfilled with argon for three times. CO was bubbled through a needleinto the solution for 3 min, and the mixture was heated under a COballoon at 70° C. for 3 h. The reaction was cooled to rt, diluted withEtOAc, washed with water, brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography toyield the desired product (0.012 g, 69%) as a yellow solid. MS(ESI) m/z:469.3 (M+H)⁺.

Example 157. Methyl(10R,14S)-5-amino-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylate,2 TFA salt: Example 157 was made in the same way as Example 89 byreplacing Example 89A with 157B. ¹H NMR (500 MHz, MeOD) δ 8.68 (d, J=6.3Hz, 1H), 8.22 (d, J=1.9 Hz, 1H), 8.16 (s, 1H), 7.92 (dd, J=6.2, 1.8 Hz,1H), 7.81 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.56 (ddd, J=8.1, 6.5, 1.4 Hz,1H), 7.46 (td, J=8.1, 1.4 Hz, 1H), 6.67 (s, 1H), 5.37 (dd, J=11.6, 6.1Hz, 1H), 3.90 (s, 3H), 2.84-2.75 (m, 1H), 2.43 (d, J=0.8 Hz, 3H),2.30-2.20 (m, 1H), 2.10-1.94 (m, 2H), 1.74-1.53 (m, 2H), 0.96 (d, J=7.2Hz, 3H), 0.55-0.43 (m, 1H) ppm. MS(ESI) m/z: 606.2 (M+H)⁺. AnalyticalHPLC RT=6.19 min (Method A).

Example 158(10R,14S)-5-Amino-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid, 2 TFA salt

Example 158.(10R,14S)-5-Amino-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid, 2 TFA salt: To the solution of Example 157 (0.009 g, 10.79 μmol)in MeOH (1 mL) was added 1 N NaOH (0.108 mL, 0.108 mmol). The reactionwas stirred at 50° C. for 24 h. The reaction was quenched with TFA andpurified by reverse phase HPLC to isolate the desired product (6 mg, 65%yield) as a yellow solid. ¹H NMR (500 MHz, MeOD) δ 8.65 (d, J=5.8 Hz,1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.85-7.79 (m, 2H), 7.59-7.53 (m, 1H),7.49-7.43 (m, 1H), 6.65 (s, 1H), 5.35 (dd, J=11.3, 6.1 Hz, 1H),2.82-2.74 (m, 1H), 2.44 (s, 3H), 2.27-2.17 (m, 1H), 2.05-1.94 (m, 2H),1.71-1.49 (m, 2H), 0.96 (d, J=6.9 Hz, 3H), 0.55-0.44 (m, 1H) ppm.MS(ESI) m/z: 592.3 (M+H)⁺. Analytical HPLC RT=5.59 min (Method A).

Example 1591-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

159A.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-isothiocyanato-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide:To a solution of Example 89 (Alternative, patent) (36 mg, 0.066 mmol) inDCM (1 mL) at 0° C. was added 1,1′-thiocarbonylbis(pyridin-2(1H)-one)(15.26 mg, 0.066 mmol) in dichloromethane (0.5 mL) dropwise. Thereaction mixture was slowly warm to rt and stirred overnight. Thereaction was concentrated and purified by silica gel chromatography toyield the desired product (10 mg, 25%). MS(ESI) m/z: 592.3 (M+H)⁺.

Example 159.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: The mixture of 159A (10 mg, 0.017 mmol) and acetohydrazide(1.255 mg, 0.017 mmol) in THF (1 mL) was stirred at rt overnight. Themixture was concentrated. The residue was taken up with DMF (1 mL) andadded EDC (13.00 mg, 0.068 mmol) and TEA (0.014 mL, 0.102 mmol). Theresulting mixture was stirred at rt overnight. The reaction mixture wasdiluted with MeOH and purified by reverse phase HPLC to yield thedesired product (4.5 mg, 34%) as a yellow solid. ¹H NMR (500 MHz, MeOD)δ 8.78 (d, J=6.1 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 7.96 (dd, J=6.1, 1.7Hz, 1H), 7.85 (ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H),7.69 (d, J=2.2 Hz, 1H), 7.63-7.56 (m, 2H), 7.49 (td, J=8.1, 1.4 Hz, 1H),5.40 (dd, J=11.3, 6.1 Hz, 1H), 3.31 (m, 3H), 2.88-2.80 (m, 1H), 2.51 (s,3H), 2.46 (d, J=0.8 Hz, 3H), 2.34-2.23 (m, 1H), 2.12-1.96 (m, 2H),1.77-1.52 (m, 2H), 1.01 (d, J=7.2 Hz, 3H), 0.54 (d, J=11.6 Hz, 1H) ppm.MS(ESI) m/z: 629.9 (M+H)⁺. Analytical HPLC RT=5.85 min (Method A).

Example 160N-[(10R,14S)-5-Carbamimidamido-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 160.N-[(10R,14S)-5-Carbamimidamido-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,TFA salt: To a mixture of 159A (31 mg, 0.053 mmol) and acetohydrazide(3.89 mg, 0.053 mmol) was added THF (1 mL) and the reaction was stirredat rt overnight. The reaction was concentrated. The residue was taken upin DCM (1.4 mL), cooled to 0° C. and added TFA (0.6 mL, 7.79 mmol). Thereaction was stirred at 0° C. for 30 min. The reaction was concentratedand purified by reverse phase HPLC to yield the desired product (11 mg,78%). ¹H NMR (500 MHz, MeOD) δ 8.81 (d, J=5.5 Hz, 1H), 8.03 (d, J=1.1Hz, 1H), 7.88-7.79 (m, 2H), 7.77 (dd, J=5.6, 1.8 Hz, 1H), 7.59 (ddd,J=8.0, 6.5, 1.7 Hz, 1H), 7.53-7.42 (m, 2H), 7.26 (d, J=2.2 Hz, 1H), 5.37(dd, J=11.0, 5.8 Hz, 1H), 3.36 (m, 6H), 2.81-2.71 (m, 1H), 2.48 (d,J=1.1 Hz, 3H), 2.29-2.19 (m, 1H), 2.05-1.88 (m, 2H), 1.65-1.49 (m, 2H),1.01 (d, J=6.9 Hz, 3H), 0.57 (d, J=12.7 Hz, 1H) ppm. MS(ESI) m/z: 590.0(M+H)⁺. Analytical HPLC RT=4.82 min (Method A).

Example 1611-(2-Fluorophenyl)-5-methyl-N-[(10S,14S)-10-methyl-5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 161.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10S,14S)-10-methyl-5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 161 was made in the same way as Example 159 by usingcorresponding amine intermediate. ¹H NMR (500 MHz, MeOD) δ 8.77 (d,J=5.8 Hz, 1H), 8.12 (d, J=1.4 Hz, 1H), 7.89 (dd, J=5.8, 1.7 Hz, 1H),7.79-7.70 (m, 2H), 7.69-7.54 (m, 4H), 7.53-7.45 (m, 2H), 5.29 (dd,J=10.7, 5.2 Hz, 1H), 3.32 (m, 3H), 2.56-2.42 (m, 7H), 2.35-2.20 (m, 1H),2.16-2.00 (m, 1H), 1.87-1.72 (m, 1H), 1.70-1.57 (m, 1H), 1.30-1.26 (m,3H), 1.13-0.98 (m, 1H) ppm. MS(ESI) m/z: 596.0 (M+H)⁺. Analytical HPLCRT=5.16 min (Method A).

Example 1621-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-[(1,3,4-oxadiazol-2-yl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 162.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-[(1,3,4-oxadiazol-2-yl)amino]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 162 was made in the same way as Example 159 byreplacing acetohydrazide with formohydrazide. ¹H NMR (500 MHz,acetonitrile-d₃) δ 8.60 (d, J=5.50 Hz, 1H), 8.53 (br. s., 1H), 8.34 (d,J=6.88 Hz, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.67 (ddd, J=1.65, 6.74,8.12 Hz, 1H), 7.56 (d, J=1.93 Hz, 1H), 7.48-7.54 (m, 1H), 7.37-7.44 (m,1H), 7.29-7.35 (m, 2H), 5.09-5.22 (m, 1H), 3.03 (dq, J=4.95, 7.24 Hz,1H), 2.35 (d, J=1.10 Hz, 3H), 2.30-2.10 (m, 3H), 1.60-1.73 (m, 2H),1.25-1.37 (m, 3H), 1.11 (d, J=7.15 Hz, 3H), 0.85 (dd, J=3.44, 11.69 Hz,1H) ppm. MS(ESI) m/z: 616.6 (M+H)⁺. Analytical HPLC RT=5.80 min (MethodA).

Example 163N-[(10R,14S)-5-Bromo-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2fluorophenyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide, TFA salt

Example 163.N-[(10R,14S)-5-Bromo-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1-(3-chloro-2fluorophenyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide, TFA salt: To amixture of copper (II) bromide (58.3 mg, 0.261 mmol) and tert-butylnitrite (0.034 mL, 0.290 mmol) in acetonitrile (1 mL) at 0° C. was addedto a solution of Example 89 (Alternative, parent) (159 mg, 0.290 mmol)in acetonitrile (1 mL). The reaction was allowed to slowly warm to rtand stirred overnight. The reaction was quenched with 1 N HCL (2.0 mL)and extracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified byreverse phase HPLC to yield the desired product (90 mg, 41%) as a whitesolid. ¹H NMR (500 MHz, MeOD) δ 8.78 (d, J=5.5 Hz, 1H), 7.95 (s, 1H),7.85 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.73-7.66 (m, 2H), 7.64-7.57 (m,2H), 7.54-7.44 (m, 2H), 5.35 (dd, J=11.0, 5.8 Hz, 1H), 3.31 (m, 2H),2.80-2.69 (m, 1H), 2.49 (d, J=1.1 Hz, 3H), 2.22 (br. s., 1H), 2.04-1.84(m, 2H), 1.65-1.45 (m, 2H), 0.99 (d, J=6.9 Hz, 3H), 0.51 (d, J=12.1 Hz,1H) ppm. MS(ESI) m/z: 612.8 (M+H)⁺. Analytical HPLC RT=7.73 min (MethodA).

Example 1641-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(1H-pyrazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 164.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(1H-pyrazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: A mixture of Example 163 (10 mg, 0.016 mmol),(1H-pyrazol-5-yl)boronic acid (3.66 mg, 0.033 mmol) and Cs₂CO₃ (16 mg,0.049 mmol) in 1,2-dimethoxyethane (1 mL) and water (0.2 mL) wasdegassed for 15 min. To this mixture was then added palladium tetrakis(2 mg, 1.63 μmol). The reaction was heated at 120° C. under microwaveconditions for 20 min. The mixture was concentrated and purified byreverse phase HPLC to yield the desired product (2.3 mg, 19%) as ayellow solid. ¹H NMR (500 MHz, MeOD) δ 8.76 (d, J=5.5 Hz, 1H), 8.07 (s,1H), 7.91 (dd, J=8.0, 1.7 Hz, 1H), 7.85-7.78 (m, 3H), 7.76-7.69 (m, 3H),7.61-7.53 (m, 1H), 7.46 (td, J=8.2, 1.5 Hz, 1H), 6.80 (d, J=2.5 Hz, 1H),5.36 (dd, J=11.0, 6.1 Hz, 1H), 3.21 (m, 2H), 2.83-2.70 (m, 1H),2.48-2.44 (m, 3H), 2.29-2.14 (m, 1H), 2.05-1.89 (m, 2H), 1.66-1.43 (m,2H), 1.03-0.96 (m, 3H), 0.53 (d, J=12.1 Hz, 1H) ppm. MS(ESI) m/z: 598.9(M+H)⁺. Analytical HPLC RT=1.37 min (Method C).

Example 1651-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10S,14S)-10-methyl-9-oxo-5-(1H-pyrazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 165.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10S,14S)-10-methyl-9-oxo-5-(1H-pyrazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 165 was made in the same way as Example 164 by usingthe other isomer. ¹H NMR (500 MHz, MeOD) δ 8.76 (d, J=5.5 Hz, 1H), 8.07(s, 1H), 7.91 (dd, J=8.0, 1.7 Hz, 1H), 7.85-7.78 (m, 3H), 7.76-7.69 (m,3H), 7.61-7.53 (m, 1H), 7.46 (td, J=8.2, 1.5 Hz, 1H), 6.80 (d, J=2.5 Hz,1H), 5.36 (dd, J=11.0, 6.1 Hz, 1H), 3.21 (m, 2H), 2.83-2.70 (m, 1H),2.48-2.44 (m, 3H), 2.29-2.14 (m, 1H), 2.05-1.89 (m, 2H), 1.66-1.43 (m,2H), 1.03-0.96 (m, 3H), 0.53 (d, J=12.1 Hz, 1H) ppm. MS(ESI) m/z: 598.9(M+H)⁺. Analytical HPLC RT=6.27 min (Method A).

Example 1661-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-[(1,3-thiazol-2-yl)amino]-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 166.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-[(1,3-thiazol-2-yl)amino]-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: A vial containing potassium carbonate (16.94 mg, 0.123 mmol),thiazol-2-amine (2.455 mg, 0.025 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine(2.376 mg, 4.90 μmol) and tris(dibenzylideneacetone)dipalladium(0)(1.122 mg, 1.226 μmol) was purged with a stream of argon and sealed witha cap. A separate pressure-tested vial containing a magnetic stirrer,Example 163 (15 mg, 0.025 mmol), t-butanol (0.3 mL), acetic acid (1drop) and (1 drop) was purged by bubbling argon through the liquid for10 min. The contents of the first vial were added quickly and the secondvial was sealed. The reaction was heated at 110° C. for 4.5 h and thencooled to rt. The reaction was concentrated and purified by reversephase HPLC to yield the desired product (2.5 mg, 12%) as a light yellowsolid. ¹H NMR (500 MHz, acetonitrile-d₃) δ 8.58 (d, J=5.50 Hz, 1H), 8.42(d, J=7.15 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.67 (ddd, J=1.65, 6.88,8.25 Hz, 1H), 7.46-7.54 (m, 4H), 7.42 (ddd, J=1.65, 6.53, 8.05 Hz, 1H),7.33 (dt, J=1.38, 8.12 Hz, 1H), 7.25 (d, J=3.85 Hz, 1H), 6.79 (d, J=3.85Hz, 1H), 5.22-5.31 (m, 1H), 2.56-2.62 (m, 1H), 2.33 (s, 3H), 1.92-2.08(m, 2H), 1.77-1.81 (m, 2H), 1.32-1.48 (m, 3H), 0.82 (d, J=6.88 Hz, 3H),0.26-0.36 (m, 1H) ppm. MS(ESI) m/z: 631.6 (M+H)⁺. Analytical HPLCRT=6.13 min (Method A).

Example 1671-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10S,14S)-10-methyl-9-oxo-5-[(1,3-thiazol-2-yl)amino]-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 167.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10S,14S)-10-methyl-9-oxo-5-[(1,3-thiazol-2-yl)amino]-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: Example 167 was made in the same way as Example 166 by usingthe other isomer. ¹H NMR (500 MHz, acetonitrile-d₃) δ 8.59 (d, J=5.50Hz, 1H), 8.38 (d, J=7.15 Hz, 1H), 7.83 (s, 1H), 7.68 (ddd, J=1.65, 6.81,8.32 Hz, 1H), 7.50-7.55 (m, 2H), 7.46-7.49 (m, 1H), 7.42 (ddd, J=1.51,6.53, 8.18 Hz, 1H), 7.30-7.36 (m, 2H), 7.23 (d, J=3.58 Hz, 1H), 6.76 (d,J=3.85 Hz, 1H), 5.09-5.19 (m, 1H), 2.36 (d, J=0.83 Hz, 3H), 2.02-2.17(m, 4H), 1.97-2.00 (m, 1H), 1.60-1.73 (m, 3H), 1.25-1.37 (m, 2H), 1.10(d, J=7.15 Hz, 3H), 0.88-0.82 (m, 1H) ppm. MS(ESI) m/z: 631.6 (M+H)⁺.Analytical HPLC RT=6.11 min (Method A).

The following Examples in Table 10 were synthesized using proceduressimilar to those shown in Example 164. Example 171 was a commonby-product of the coupling reaction.

TABLE 10 Example Stereo- M + RT, min # chemistry R H Method A 168Homochiral

670.0 8.34 169 Homochiral

598.9 6.06 170 Homochiral

639.9 7.45 171 Homochiral H 532.9 6.55

Example 1721-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(2-oxo-1,2-dihydropyridin-3-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt

Example 172.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(2-oxo-1,2-dihydropyridin-3-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-1,2,3-triazole-4-carboxamide,TFA salt: To a solution of Example 170 (4 mg, 6.25 μmol) in water (0.50mL) and dioxane (0.2 mL) was added concentrated HCl (0.011 mL, 0.375mmol). The reaction was stirred at 100° C. for 1 h. The reaction mixturewas concentrated and purified by reverse phase HPLC to yield the desiredproduct (1.4 mg, 29%) as an off white solid. ¹H NMR (500 MHz, MeOD) δ8.78 (d, J=5.5 Hz, 1H), 8.06 (s, 1H), 7.92-7.82 (m, 3H), 7.79 (dd,J=5.5, 1.7 Hz, 1H), 7.77-7.73 (m, 2H), 7.60 (ddd, J=8.0, 6.4, 1.5 Hz,1H), 7.54-7.47 (m, 2H), 6.60-6.52 (m, 1H), 5.39 (dd, J=11.0, 5.8 Hz,1H), 3.32 (m, 3H), 2.84-2.75 (m, 1H), 2.49 (d, J=0.8 Hz, 3H), 2.30-2.15(m, 1H), 2.06-1.92 (m, 2H), 1.66-1.49 (m, 2H), 1.00 (d, J=7.2 Hz, 3H),0.55 (d, J=12.1 Hz, 1H) ppm. MS(ESI) m/z: 625.9 (M+H)⁺. Analytical HPLCRT=5.87 min (Method A).

Example 173 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9,11-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

173A. tert-ButylN-[(10R,14S)-11-hydroxy-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-14-yl]carbamateand tert-butylN-[(10R,14S)-12-hydroxy-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-14-yl]carbamate(1:1 mixture): To a solution of 2J (634 mg, 1.36 mmol) in THF (13.6 mL)at 0° C. was added borane tetrahydrofuran complex (4.08 mL, 4.08 mmol)dropwise. The reaction was allowed to warm up to rt and stirred for 2.5h. The reaction mixture was cooled to 0° C. and added sodium acetate(9.06 ml, 27.2 mmol), followed by hydrogen peroxide (4.16 mL, 40.8 mmol)dropwise. The reaction was warmed up to rt and stirred at for 8 h. Themixture was diluted with H₂O and extracted with EtOAc (2×). The combinedorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography(0-10% MeOH/DCM) to yield a mixture of two products (323 mg, 49%) as alight grey solid. MS(ESI) m/z: 485.1 (M+H)⁺.

173B. tert-ButylN-[(10R,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9,11-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-14-yl]carbamateand tert-butylN-[(10R,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9,12-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-14-yl]carbamate(1:1 mixture): 173A (1:1 mixture of diastereomers) (116 mg, 0.239 mmol)was dissolved in DCM (2.4 mL) and added Martin's reagent (132 mg, 0.311mmol) at rt. The reaction was stirred at rt for 1.5 h. The mixture wasdiluted with DCM, washed with H₂O, brine, dried over MgSO₄, filtered,and concentrated. The residue was purified by silica gel chromatographyto yield a 1:1 mixture of regioisomers (78 mg, 68%) as a white solid.MS(ESI) m/z: 483.1 (M+H)⁺.

173C. MethylN-[(10R,14S)-14-amino-10-methyl-9,11-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-5-yl]carbamateand 173D, methylN-[(10R,14S)-14-amino-10-methyl-9,12-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-5-yl]carbamate:173B (1:1 mixture of regioisomers) (78 mg, 0.162 mmol) was suspended inDCM (3 mL) and added TFA (0.623 mL, 8.08 mmol). The reaction became aclear light brownish solution and was stirred at rt for 1 h. Thereaction was concentrated and purified by reverse phase HPLC to yield173C, early eluting regioisomer (40 mg, 38%) as brownish oil and 173D,late eluting regioisomer (27 mg, 26%) as brownish oil. MS(ESI) m/z:383.1 (M+H)⁺.

Example 173. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9,11-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 173 was made in the same way as Example 63 byreplacing 2M with 173C. ¹H NMR (500 MHz, MeOD) δ 9.69 (s, 1H), 8.76 (d,J=6.1 Hz, 1H), 7.90-7.77 (m, 2H), 7.70-7.40 (m, 6H), 5.30 (dd, J=10.0,6.5 Hz, 1H), 3.80 (s, 3H), 3.75 (d, J=6.6 Hz, 1H), 3.06-2.95 (m, 1H),2.72-2.58 (m, 1H), 2.52-2.36 (m, 5H), 1.24 (d, J=6.6 Hz, 3H) ppm.MS(ESI) m/z: 619.9 (M+H)⁺. Analytical HPLC RT=6.98 min (Method A).

Example 174 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9,12-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 174. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9,12-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 174 was made in the same way as Example 173 byreplacing 173C with 173D. ¹H NMR (500 MHz, MeOD) δ 8.78 (d, J=5.5 Hz,1H), 8.06 (s, 1H), 7.92-7.82 (m, 3H), 7.79 (dd, J=5.5, 1.7 Hz, 1H),7.77-7.73 (m, 2H), 7.60 (ddd, J=8.0, 6.4, 1.5 Hz, 1H), 7.54-7.47 (m,2H), 6.60-6.52 (m, 1H), 5.39 (dd, J=11.0, 5.8 Hz, 1H), 3.32 (m, 3H),2.84-2.75 (m, 1H), 2.49 (d, J=0.8 Hz, 3H), 2.30-2.15 (m, 1H), 2.06-1.92(m, 2H), 1.66-1.49 (m, 2H), 1.00 (d, J=7.2 Hz, 3H), 0.55 (d, J=12.1 Hz,1H) ppm. MS(ESI) m/z: 620.1 (M+H)⁺. Analytical HPLC RT=7.86 min (MethodA).

Example 175 MethylN-[(10R,12R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-12-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

175A. To a solution of 2J (68.9 mg, 0.148 mmol) in THF (1477 μL) at 0°C. was added borane tetrahydrofuran complex (443 μL, 0.443 mmol)dropwise. The reaction was allowed to warm up to rt and stirred for 4 h.3 M NaOAc (985 μL, 2.95 mmol) and H₂O₂ (453 μL, 4.43 mmol) were addeddropwise. The reaction was stirred at rt for 2 h and diluted with H₂O.The mixture was extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography. Further purification was carriedout by using Chiral OD column (mobile phase: 50% MeOH/EtOH:50% Heptane)to give 175A (the second peak) as diastereomer mixture (7 mg, 10%). Theother regioisomers, 175B (the first peak) (5 mg, 6%) and 175C (the thirdpeak) (3 mg, 4%), were separated as methylN-[(10R,14S)-14-{[(tert-butoxy)carbonyl]amino}-11-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamateas homochiral compounds. MS(ESI) m/z: 485.1 (M+H)⁺.

Example 175. MethylN-[(10R,12R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-12-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt, TFA salt: To a solution of 175A (7.1 mg, 0.015 mmol) in CH₂Cl₂(0.5 mL) was added TFA (0.034 mL, 0.440 mmol). The reaction was stirredat rt for 40 min and concentrated. The residue redissolved in DMF (0.3mL), and added Intermediate 25 (3.73 mg, 0.015 mmol), followed by EDC(4.21 mg, 0.022 mmol), HOBT (3.37 mg, 0.022 mmol), and Hunig's base(0.026 mL, 0.147 mmol). The reaction was stirred at rt overnight. Thereaction was concentrated and purified by reverse phase HPLC to yieldthe desired product, the late eluting isomer, as a white solid (2 mg,18%). The stereochemistry was determined by X-ray crystallography. ¹HNMR (500 MHz, MeOD) δ 8.78 (d, J=5.5 Hz, 1H), 8.06 (s, 1H), 7.92-7.82(m, 3H), 7.79 (dd, J=5.5, 1.7 Hz, 1H), 7.77-7.73 (m, 2H), 7.60 (ddd,J=8.0, 6.4, 1.5 Hz, 1H), 7.54-7.47 (m, 2H), 6.60-6.52 (m, 1H), 5.39 (dd,J=11.0, 5.8 Hz, 1H), 3.32 (m, 3H), 2.84-2.75 (m, 1H), 2.49 (d, J=0.8 Hz,3H), 2.30-2.15 (m, 1H), 2.06-1.92 (m, 2H), 1.66-1.49 (m, 2H), 1.00 (d,J=7.2 Hz, 3H), 0.55 (d, J=12.1 Hz, 1H) ppm. MS(ESI) m/z: 621.2 (M+H)⁺.Analytical HPLC RT=5.13 min (Method A).

Example 176 MethylN-[(10R,12S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-12-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 176. MethylN-[(10R,12S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-12-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 176 was made in the same way as Example 175 andisolated as the early eluting isomer at the final step. ¹H NMR (500 MHz,MeOD) δ 9.63 (s, 1H), 8.71 (d, J=5.8 Hz, 1H), 8.23 (s, 1H), 7.83 (s,1H), 7.76 (dd, J=5.9, 1.5 Hz, 1H), 7.71 (ddd, J=8.1, 6.7, 1.7 Hz, 1H),7.58 (s, 1H), 7.55 (d, J=1.1 Hz, 2H), 7.45 (ddd, J=8.0, 6.4, 1.8 Hz,1H), 7.41-7.36 (m, 1H), 5.32 (dd, J=11.1, 4.8 Hz, 1H), 3.77 (s, 3H),3.63-3.55 (m, 1H), 2.60-2.52 (m, 1H), 2.37 (d, J=0.8 Hz, 3H), 2.33 (dt,J=14.0, 4.7 Hz, 1H), 2.18 (ddd, J=14.0, 11.2, 5.6 Hz, 1H), 1.47 (dd,J=12.8, 7.3 Hz, 1H), 1.33-1.25 (m, 1H), 1.12 (d, J=6.9 Hz, 3H) ppm.MS(ESI) m/z: 621.2 (M+H)⁺. Analytical HPLC RT=5.10 min (Method A).

Example 177 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-11-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 177. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-11-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 177 was made in the same way as Example 175 byreplacing 175A with 175B. ¹H NMR (500 MHz, MeOD) δ 9.70 (s, 1H), 8.70(d, J=6.1 Hz, 1H), 8.24-8.21 (m, 1H), 8.17 (s, 1H), 7.89 (dd, J=6.1, 1.7Hz, 1H), 7.78-7.68 (m, 2H), 7.63-7.46 (m, 3H), 7.45-7.36 (m, 1H), 5.46(dd, J=7.3, 5.6 Hz, 1H), 3.83-3.78 (s, 3H), 2.94 (quin, J=6.5 Hz, 1H),2.81-2.72 (m, 1H), 2.46-2.37 (m, 5H), 2.21-2.12 (m, 1H), 1.99-1.91 (m,1H), 1.71 (dt, J=14.6, 7.6 Hz, 1H), 1.20 (d, J=6.9 Hz, 3H) ppm. MS(ESI)m/z: 621.2 (M+H)⁺. Analytical HPLC RT=6.04 min (Method A).

Example 178 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-11-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 178. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-11-hydroxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 178 was made in the same way as Example 175 byreplacing 175A with 175C. ¹H NMR (500 MHz, MeOD) δ 9.70 (s, 1H), 8.70(d, J=6.3 Hz, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 7.94 (dd, J=6.2, 1.8 Hz,1H), 7.78-7.72 (m, 1H), 7.68-7.62 (m, 2H), 7.55 (dd, J=8.4, 2.1 Hz, 1H),7.49 (ddd, J=8.1, 6.5, 1.7 Hz, 1H), 7.44-7.39 (m, 1H), 5.47 (dd, J=10.2,5.8 Hz, 1H), 3.80 (s, 3H), 3.54-3.46 (m, 1H), 3.24-3.09 (m, 1H), 2.66(quin, J=6.9 Hz, 1H), 2.48-2.40 (m, 1H), 2.38 (s, 3H), 2.08-1.99 (m,1H), 1.74-1.66 (m, 1H), 1.06 (d, J=7.2 Hz, 3H) ppm. MS(ESI) m/z: 621.2(M+H)⁺. Analytical HPLC RT=6.09 min (Method A).

Example 179 MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-11-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

179A. MethylN-[(10S,14S)-14-{[(tert-butoxy)carbonyl]amino}-11-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate:To a solution of 175B (25 mg, 0.052 mmol) in DCM (1 mL) at −78° C. wasadded DAST (10.76 μL, 0.077 mmol). The reaction was stirred at −78° C.for 10 min, and then warmed slowly to rt. The reaction was stirred at rtfor 1 h and concentrated. The residue was purified by reverse phase HPLCto yield the product as a homochiral compound (2.3 mg, 7%). ¹H NMR (500MHz, MeOD) δ 9.67 (s, 1H), 8.72 (d, J=5.8 Hz, 1H), 8.33 (s, 1H), 7.98(s, 1H), 7.79-7.70 (m, 2H), 7.65-7.59 (m, 2H), 7.55-7.45 (m, 2H),7.44-7.37 (m, 1H), 5.36 (dd, J=11.6, 6.1 Hz, 1H), 5.26-5.08 (m, 1H),3.80 (s, 3H), 3.22-3.18 (m, 1H), 2.49-2.42 (m, 1H), 2.38 (s, 3H),2.07-1.97 (m, 1H), 1.84-1.68 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.84-0.63(m, 1H) ppm. MS(ESI) m/z: 487.0 (M+H)⁺. Analytical HPLC RT=6.97 min(Method A).

Example 180 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-18-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 180. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-18-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 180 was made in the same way as Example 2 by using4-bromo-5-fluoropicolinaldehyde as starting material and replacingIntermediate 11 with Intermediate 21. The intermediates were carried onas diastereomers to give Example 180 as a diastereomer mixture. ¹H NMR(500 MHz, MeOD) δ 8.90 (d, J=3.0 Hz, 1H), 8.09 (d, J=6.5 Hz, 1H),7.88-7.76 (m, 1H), 7.71-7.60 (m, 2H), 7.59-7.52 (m, 1H), 7.52-7.40 (m,2H), 5.32 (dd, J=11.3, 6.0 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 2H), 2.70(br. s., 1H), 2.44 (s, 3H), 2.26 (d, J=10.0 Hz, 1H), 2.05-1.88 (m, 1H),1.87-1.70 (m, 1H), 1.50 (br. s., 2H), 0.96 (d, J=6.8 Hz, 3H), 0.66 (br.s., 1H) ppm. MS(ESI) m/z: 624.1 (M+H)⁺. Analytical HPLC RT=8.07 min(Method A).

Example 181 MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-18-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 181. MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-18-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 180 was subjected to chiral HPLC separation usingCHIRALCEL® OJ-H column and 15% Methanol/85% CO₂ as mobile phase. Peak 1was obtained as Example 181. ¹H NMR (400 MHz, MeOD) δ 8.86 (d, J=3.0 Hz,1H), 7.91 (d, J=6.3 Hz, 1H), 7.85-7.75 (m, 1H), 7.67-7.58 (m, 2H),7.58-7.40 (m, 3H), 5.23 (dd, J=10.2, 5.1 Hz, 1H), 3.77 (s, 4H), 3.66 (s,1H), 2.44 (s, 3H), 2.26-2.08 (m, 1H), 1.98 (br. s., 1H), 1.67-1.39 (m,2H), 1.29 (d, J=5.0 Hz, 2H), 1.19 (d, J=7.0 Hz, 3H), 1.13-0.98 (m, 1H)ppm. MS(ESI) m/z: 624.2 (M+H)⁺. Analytical HPLC RT=8.07 min (Method A).

Example 182 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-18-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 182. MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-18-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 180 was subjected to chiral HPLC separation usingCHIRALCEL® OJ-H column and 15% Methanol/85% CO₂ as mobile phase. Peak 2was obtained as Example 182. ¹H NMR (400 MHz, MeOD) δ 8.90 (d, J=3.0 Hz,1H), 8.09 (d, J=6.5 Hz, 1H), 7.88-7.76 (m, 1H), 7.71-7.60 (m, 2H),7.59-7.52 (m, 1H), 7.52-7.40 (m, 2H), 5.32 (dd, J=11.3, 6.0 Hz, 1H),3.78 (s, 3H), 3.66 (s, 2H), 2.70 (br. s., 1H), 2.44 (s, 3H), 2.26 (d,J=10.0 Hz, 1H), 2.05-1.88 (m, 1H), 1.87-1.70 (m, 1H), 1.50 (br. s., 2H),0.96 (d, J=6.8 Hz, 3H), 0.66 (br. s., 1H) ppm. MS(ESI) m/z: 624.2(M+H)⁺. Analytical HPLC RT=8.07 min (Method A).

Example 183 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10,18-dimethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 183. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10,18-dimethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 183 was made in the same way as Example 2 by using4-bromo-5-methylpicolinaldehyde as starting material and replacingIntermediate 11 with Intermediate 21. The intermediates were carried onas diastereomers to give Example 183 as a diastereomer mixture. ¹H NMR(400 MHz, MeOD) δ 8.67 (s, 1H), 7.87-7.77 (m, 2H), 7.63-7.41 (m, 5H),5.32 (dd, J=11.3, 6.0 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 2H), 2.70 (br. s.,1H), 2.50 (s, 3H), 2.44 (s, 3H), 2.26 (d, J=10.0 Hz, 1H), 2.05-1.88 (m,1H), 1.87-1.70 (m, 1H), 1.50 (br. s., 2H), 0.96 (d, J=6.8 Hz, 3H), 0.66(br. s., 1H) ppm. MS(ESI) m/z: 620.1 (M+H)⁺. Analytical HPLC RT=5.53 min(Method A).

Example 184 Methyl(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylate,TFA salt

Example 184. Methyl(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylate,TFA salt: Example 184 was made in the same way as Example 2 by replacing2-amino-4-nitrophenylboronic acid with(2-amino-4-(methoxycarbonyl)phenyl)boronic acid in step 2C and replacingIntermediate 11 with Intermediate 25. The diastereomer mixture wasseparated during step 2J. Diastereomer A, the early eluting isomer onsilica gel chromatography, was used to generate the homochiral finalproduct. ¹H NMR (500 MHz, MeOD) δ 8.84 (d, J=5.8 Hz, 1H), 8.40-8.30 (m,2H), 8.27-8.12 (m, 2H), 7.99 (dd, J=5.9, 1.8 Hz, 1H), 7.74 (d, J=1.4 Hz,1H), 7.53-7.30 (m, 3H), 5.28 (dd, J=11.4, 6.2 Hz, 1H), 3.98 (s, 3H),2.84-2.73 (m, 1H), 2.37 (s, 3H), 2.28-2.17 (m, 1H), 2.08-1.97 (m, 1H),1.96-1.83 (m, 1H), 1.68-1.49 (m, 2H), 0.98 (d, J=6.9 Hz, 3H), 0.62-0.46(m, 1H) ppm. MS(ESI) m/z: 590.2 (M+H)⁺. Analytical HPLC RT=5.53 min(Method A).

Example 185(10R,14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid, TFA salt

Example 185.(10R,14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid: To a solution of Example 184 (12.15 mg, 0.017 mmol) in THF (173μL) was added LiOH (34.5 μL, 0.069 mmol). The reaction was stirred at rtfor 2 h. 0.1 mL of 1 N HCl was added and the mixture was concentrated.The residue was purified by reverse phase HPLC to give the desiredproduct (8.8 mg, 73%) as a clear glass. ¹H NMR (400 MHz, MeOD) δ 8.82(d, J=6.1 Hz, 1H), 8.36-8.29 (m, 2H), 8.27-8.17 (m, 2H), 8.01 (d, J=5.8Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.50-7.33 (m, 3H), 5.27 (dd, J=11.1,6.1 Hz, 1H), 2.82-2.72 (m, J=6.6 Hz, 1H), 2.34 (s, 3H), 2.28-2.16 (m,1H), 2.09-1.96 (m, 1H), 1.90 (t, J=12.1 Hz, 1H), 1.68-1.46 (m, 2H), 0.96(d, J=6.8 Hz, 3H), 0.53 (d, J=11.4 Hz, 1H) ppm. MS(ESI) m/z: 576.1(M+H)⁺. Analytical HPLC RT=5.84 min (Method A).

Example 186(10S,14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid, TFA salt

Example 186.(10S,14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid, TFA salt: Example 186 was made in the same way as Example 185 byusing the other isomer. ¹H NMR (500 MHz, MeOD) δ 8.82 (d, J=5.8 Hz, 1H),8.35 (d, J=1.9 Hz, 1H), 8.29 (s, 1H), 8.24 (dd, J=8.3, 1.9 Hz, 1H), 8.04(s, 1H), 7.91 (d, J=5.5 Hz, 1H), 7.74 (ddd, J=8.3, 6.7, 1.8 Hz, 1H),7.51-7.45 (m, 2H), 7.41 (dd, J=8.1, 1.2 Hz, 1H), 5.20 (dd, J=10.5, 5.5Hz, 1H), 2.47-2.34 (m, 4H), 2.26-2.14 (m, 1H), 2.07-1.96 (m, 1H),1.76-1.63 (m, 1H), 1.57 (d, J=11.0 Hz, 1H), 1.35-1.21 (m, 4H), 1.10-0.96(m, 1H) ppm. MS(ESI) m/z: 576.2 (M+H)⁺. Analytical HPLC RT=5.44 min(Method A).

Example 187(10R,14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carboxylicacid, TFA salt

Example 187.(10R,14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carboxylicacid, TFA salt: Example 187 was made in the same way as Example 185 byreplacing (2-amino-4-(methoxycarbonyl)phenyl)boronic acid with2-amino-5-(methoxycarbonyl)phenylboronic acid in step 2C. ¹H NMR (500MHz, MeOD) δ 8.81 (d, J=6.1 Hz, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 8.12(dd, J=8.0, 1.4 Hz, 1H), 7.95-7.87 (m, 2H), 7.81 (d, J=8.0 Hz, 1H),7.75-7.67 (m, 1H), 7.49-7.42 (m, 1H), 7.41-7.34 (m, 1H), 5.26 (dd,J=11.1, 5.9 Hz, 1H), 2.81-2.70 (m, 1H), 2.35 (s, 3H), 2.26-2.14 (m, 1H),2.06-1.94 (m, 1H), 1.93-1.83 (m, 1H), 1.63-1.44 (m, 2H), 0.97 (d, J=6.9Hz, 3H), 0.53 (d, J=10.5 Hz, 1H) ppm. MS(ESI) m/z: 576.3 (M+H)⁺.Analytical HPLC RT=5.84 min (Method A).

Example 188(14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid, TFA salt

Example 188.(14S)-14-[1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylicacid, TFA salt: Example 188 was made in the same way as Example 21 byreplacing 2-amino-4-nitrophenylboronic acid with2-amino-5-(methoxycarbonyl)phenylboronic acid. Hydrolysis of the methylester to acid was carried out at the last step. ¹H NMR (400 MHz, MeOD) δ8.82 (d, J=6.1 Hz, 1H), 8.34-8.28 (m, 2H), 8.21 (dd, J=8.2, 1.9 Hz, 1H),8.17 (d, J=1.3 Hz, 1H), 7.95 (dd, J=6.1, 1.8 Hz, 1H), 7.71 (ddd, J=8.2,6.7, 1.8 Hz, 1H), 7.49-7.33 (m, 3H), 5.26 (dd, J=11.1, 5.8 Hz, 1H),2.60-2.50 (m, 1H), 2.35 (d, J=0.8 Hz, 3H), 2.29-2.17 (m, 1H), 2.08-1.93(m, 2H), 1.89-1.63 (m, 2H), 1.52-1.37 (m, 1H), 0.87-0.71 (m, 1H) ppm.MS(ESI) m/z: 562.2 (M+H)⁺. Analytical HPLC RT=6.05 min (Method A).

Example 189(10R,14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-N,10-dimethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4,14-diamido,TFA salt

Example 189.(10R,14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-N,10-dimethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-4,14-diamido,TFA salt: Example 185 (5.76 mg, 8.35 μmol), methanamine (29.2 μL, 0.058mmol) (2 M in THF), EDC (3.20 mg, 0.017 mmol), and HOBT (2.56 mg, 0.017mmol) were weighed into a 2 dram vial. DMF (167 μL) followed by Hunig'sbase (7.29 μL, 0.042 mmol) were added. The mixture was stirred at rtovernight. The reaction mixture was diluted with MeOH and purified byreverse phase HPLC to give the desired product (1.6 mg, 27%) as a whitesolid. ¹H NMR (500 MHz, MeOD) δ 8.82 (d, J=6.1 Hz, 1H), 8.32 (s, 1H),8.19-8.12 (m, 2H), 8.03 (dd, J=8.3, 2.2 Hz, 1H), 7.94 (dd, J=5.9, 1.8Hz, 1H), 7.74 (td, J=7.5, 1.8 Hz, 1H), 7.52-7.45 (m, 1H), 7.44-7.37 (m,2H), 5.27 (dd, J=11.1, 5.9 Hz, 1H), 2.98 (s, 3H), 2.82-2.74 (m, 1H),2.38 (s, 3H), 2.27-2.16 (m, 1H), 2.06-1.86 (m, 2H), 1.66-1.48 (m, 2H),0.98 (d, J=6.9 Hz, 3H), 0.54 (d, J=11.8 Hz, 1H) ppm. MS(ESI) m/z: 589.2(M+H)⁺. Analytical HPLC RT=5.25 min (Method A).

Example 190(10R,14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt

Example 190.(10R,14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt: Example 187 (12 mg, 0.021 mmol), NH₄Cl (7.80 mg, 0.146 mmol),EDC (7.99 mg, 0.042 mmol), and HOBT (6.38 mg, 0.042 mmol) were weighedinto a 1 dram vial. DMF (208 μL) was added followed by Hunig's base(18.19 μL, 0.104 mmol). The resulting clear pale yellow solution wasstirred at rt overnight. The mixture was diluted with MeOH and purifiedby reverse phase HPLC to yield the desired product (11.3 mg, 77%) as awhite solid. ¹H NMR (500 MHz, MeOD) δ 8.82 (d, J=6.1 Hz, 1H), 8.31 (s,1H), 8.24 (s, 1H), 8.04-7.90 (m, 2H), 7.87-7.76 (m, 2H), 7.71 (ddd,J=8.2, 6.7, 1.7 Hz, 1H), 7.51-7.42 (m, 1H), 7.40-7.28 (m, 1H), 5.27 (dd,J=11.1, 5.9 Hz, 1H), 2.76 (t, J=6.5 Hz, 1H), 2.35 (d, J=0.6 Hz, 3H),2.27-2.12 (m, 1H), 2.10-1.96 (m, 1H), 1.97-1.81 (m, 1H), 1.68-1.44 (m,2H), 0.97 (d, J=6.9 Hz, 3H), 0.55 (d, J=10.7 Hz, 1H) ppm. MS(ESI) m/z:575.3 (M+H)⁺. Analytical HPLC RT=5.32 min (Method A).

Example 191(10S,14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt

Example 191.(10S,14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt: Example 191 was made in the same way as Example 190 by usingthe other isomer. ¹H NMR (500 MHz, MeOD) δ 8.82 (d, J=5.8 Hz, 1H), 8.28(s, 1H), 8.09 (s, 1H), 8.02 (dd, J=8.0, 1.7 Hz, 1H), 7.93 (d, J=5.2 Hz,1H), 7.87-7.80 (m, 2H), 7.71 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.45 (ddd,J=8.0, 6.5, 1.7 Hz, 1H), 7.41-7.34 (m, 1H), 5.19 (dd, J=10.7, 5.2 Hz,1H), 2.45-2.37 (m, 1H), 2.35 (d, J=0.6 Hz, 3H), 2.24-2.13 (m, 1H),2.07-1.96 (m, 1H), 1.68 (q, J=10.8 Hz, 1H), 1.60-1.50 (m, 1H), 1.30 (dd,J=8.4, 4.3 Hz, 1H), 1.24 (d, J=6.9 Hz, 3H), 1.06-0.93 (m, 1H) ppm.MS(ESI) m/z: 575.3 (M+H)⁺. Analytical HPLC RT=5.25 min (Method A).

Example 192(14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt

Example 192.(14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt: Example 192 was made in the same way as Example 190 byreplacing Example 187 with Example 188. ¹H NMR (400 MHz, MeOD) δ 8.85(d, J=6.0 Hz, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=2.2 Hz, 1H),8.09 (dd, J=8.2, 2.2 Hz, 1H), 8.03 (dd, J=6.0, 1.6 Hz, 1H), 7.72 (ddd,J=8.2, 6.6, 1.6 Hz, 1H), 7.48-7.35 (m, 3H), 5.27 (dd, J=11.0, 6.0 Hz,1H), 2.60-2.52 (m, 1H), 2.34 (s, 3H), 2.31-2.20 (m, 1H), 2.09-1.94 (m,2H), 1.89-1.67 (m, 2H), 1.45 (dd, J=7.1, 3.8 Hz, 1H), 0.86-0.71 (m, 1H)ppm. MS(ESI) m/z: 561.2 (M+H)⁺. Analytical HPLC RT=5.56 min (Method A).

Example 193(14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-5-N,5-N-dimethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt

Example 193.(14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-5-N,5-N-dimethyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt: Example 193 was made in the same way as Example 192 byreplacing NH₄Cl with dimethylamine. ¹H NMR (400 MHz, MeOD) δ 8.80 (d,J=6.0 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J=1.1 Hz, 1H), 7.92 (dd, J=6.0,1.6 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.75-7.63 (m, 2H), 7.49-7.35 (m,3H), 5.24 (dd, J=11.0, 5.5 Hz, 1H), 3.13 (s, 3H), 3.08 (s, 3H),2.60-2.49 (m, 1H), 2.38-2.31 (s, 3H), 2.29-2.16 (m, 1H), 2.07-1.92 (m,2H), 1.89-1.63 (m, 2H), 1.52-1.37 (m, 1H) ppm. MS(ESI) m/z: 589.3(M+H)⁺. Analytical HPLC RT=5.90 min (Method A).

Example 1941-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(1H-1,2,4-triazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt

Example 194.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-9-oxo-5-(1H-1,2,4-triazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt: Example 190 (8.3 mg, 0.014 mmol) was stirred inN,N-dimethylformamide dimethyl acetal (0.5 mL, 3.73 mmol) at 75° C. for3 h. The reaction mixture was concentrated. The residue was taken up inAcOH (0.1 mL, 1.747 mmol) and hydrazine monohydrate (0.025 mL, 0.510mmol). The mixture was stirred at 75° C. for 1 h and concentrated. Theresidue was purified by reverse phase HPLC to yield the desired product(7.2 mg, 60%) as a pale yellow solid. ¹H NMR (500 MHz, MeOD) δ 8.80 (d,J=5.8 Hz, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.17 (dd,J=8.3, 1.7 Hz, 1H), 8.02-7.93 (m, 2H), 7.84 (d, J=8.3 Hz, 1H), 7.71(ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.46 (ddd, J=8.0, 6.5, 1.7 Hz, 1H),7.41-7.34 (m, 1H), 5.27 (dd, J=11.3, 6.1 Hz, 1H), 2.83-2.74 (m, 1H),2.35 (d, J=0.8 Hz, 3H), 2.28-2.15 (m, 1H), 2.08-1.98 (m, 1H), 1.97-1.87(m, 1H), 1.70-1.45 (m, 2H), 0.99 (d, J=6.9 Hz, 3H), 0.56 (d, J=11.6 Hz,1H) ppm. MS(ESI) m/z: 599.3 (M+H)⁺. Analytical HPLC RT=5.26 min (MethodA).

Example 1951-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt

Example 195.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(10R,14S)-10-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt: Example 195 was made in the same way as Example 194 byreplacing N,N-dimethylformamide dimethyl acetal with1,1-dimethoxy-N,N-dimethylethanamine. ¹H NMR (500 MHz, MeOD) δ 8.80 (d,J=6.1 Hz, 1H), 8.31 (s, 1H), 8.29 (d, J=1.4 Hz, 1H), 8.13 (dd, J=8.1,1.8 Hz, 1H), 8.01 (dd, J=6.1, 1.9 Hz, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.84(d, J=8.0 Hz, 1H), 7.72 (ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.46 (ddd, J=8.1,6.5, 1.7 Hz, 1H), 7.42-7.34 (m, 1H), 5.27 (dd, J=11.3, 6.1 Hz, 1H),2.83-2.74 (m, 1H), 2.55 (s, 3H), 2.35 (d, J=0.8 Hz, 3H), 2.29-2.18 (m,1H), 2.03 (m, 1H), 1.97-1.86 (m, 1H), 1.68-1.48 (m, 2H), 0.99 (d, J=6.9Hz, 3H), 0.57 (d, J=11.3 Hz, 1H) ppm. MS(ESI) m/z: 613.3 (M+H)⁺.Analytical HPLC RT=5.16 min (Method A).

Example 1961-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-(hydroxymethyl)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-pyrazole-4-carboxamide

Example 196.1-(3-Chloro-2-fluorophenyl)-N-[(10R,14S)-5-(hydroxymethyl)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-1H-pyrazole-4-carboxamide:To a suspension of Example 187 (35 mg, 0.061 mmol) and BOP (32.2 mg,0.073 mmol) in THF (1 mL) was added DIPEA (0.032 mL, 0.182 mmol). Thereaction was stirred at rt for 5 min and added NaBH₄ (9.20 mg, 0.243mmol). The reaction was stirred for 1 h, quenched MeOH, and thenconcentrated. The residue was purified by reverse phase HPLC to yieldthe desired product (9 mg, 25% yield) as a white solid. ¹H NMR (500 MHz,MeOD) δ 8.63 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.78-7.68 (m, 1H), 7.65(s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.52-7.33 (m, 4H), 7.25 (s, 1H), 5.21(dd, J=11.1, 5.6 Hz, 1H), 4.67 (s, 2H), 2.70 (m, 1H), 2.38 (d, J=0.8 Hz,3H), 2.00 (d, J=14.3 Hz, 1H), 1.96-1.80 (m, 2H), 1.51 (m, 1H), 1.40 (m,1H), 0.95 (d, J=6.9 Hz, 3H), 0.44 (m, 1H) ppm. MS(ESI) m/z: 562.2(M+H)⁺. Analytical HPLC RT=5.23 min (Method A).

Example 1971-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(14S)-10-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt

197A.(14S)-14-C-1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5,14-diamido,TFA salt: 197A was made in the same way as Example 189 by replacing(2-amino-4-(methoxycarbonyl)phenyl)boronic acid with2-amino-5-(methoxycarbonyl)phenylboronic acid in step 2C. Thediastereomer mixture was not separated and carried on through thesyntheses. MS(ESI) m/z: 575.6 (M+H)⁺.

Example 197.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(14S)-10-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt: 197A (8 mg, 0.012 mmol) was stirred in N,N-Dimethylacetamidedimethyl acetal (0.424 mL, 2.90 mmol) at 75° C. for 4 h. The reactionmixture was diluted with ether and mixed. The organic solution wasdecanted from the pale yellow-white solid. The solid was dried andtreated with hydroxylamine hydrochloride (0.807 mg, 0.012 mmol), sodiumhydroxide (0.017 mL, 0.017 mmol), acetic acid (1.329 μL, 0.023 mmol),and dioxane (0.5 mL). The mixture was stirred at rt for 1 h and stand atrt overnight. The reaction mixture was concentrated. The residue waspurified by reverse phase HPLC to give the desired product (3.4 mg, 39%)as diastereomer mixture. ¹H NMR (500 MHz, MeOD) δ 8.64 (d, J=5.50 Hz,1H), 8.26 (s, 1H), 8.02-8.09 (m, 1H), 8.01 (d, J=5.65 Hz, 1H), 7.96 (d,J=1.65 Hz, 1H), 7.91 (s, 0.5H), 7.86 (d, J=1.65 Hz, 1H), 7.81 (s, 0.5H),7.69-7.72 (m, 1H), 7.56 (dt, J=1.51, 7.50 Hz, 1H), 7.51 (d, J=4.13 Hz,0.5H), 7.41 (dd, J=1.38, 5.23 Hz, 0.5H), 7.31-7.35 (m, 1H), 7.22-7.27(m, 1H), 5.18-5.24 (m, 1H), 5.08-5.15 (m, 1H), 2.53-2.58 (m, 1H),2.34-2.36 (m, 1H), 2.35 (s, 3H), 2.27, 2.26 (2s, 3H), 2.12 (d, J=7.43Hz, 1H), 1.98 (ddd, J=2.48, 4.95, 7.43 Hz, 1H), 1.69-1.72 (m, 1H),1.56-1.63 (m, 1H), 1.28-1.42 (m, 1H), 1.11 (d, J=6.88 Hz, 1.2H), 0.81(d, J=6.88 Hz, 1.8H), 0.28 (m, 1H) ppm. MS(ESI) m/z: 614.6 (M+H)⁺.Analytical HPLC RT=6.78 min (Method A).

Example 1981-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(14S)-9-oxo-4-(2H-1,2,3,4-tetrazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt

198A. tert-ButylN-[(11E,14S)-4-cyano-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate:198A was made in the same way as 2J by replacing2-amino-4-nitrophenylboronic acid with 2-amino-5-cyanophenylboronic acidin step 2C and replacing 2-methylbut-3-enoic acid with but-3-enoic acidin step 21. MS(ESI) m/z: 405.3 (M+H)⁺.

Example 198B. tert-ButylN-[(11E,14S)-9-oxo-4-(2H-1,2,3,4-tetrazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate:To a solution of 198A (56 mg, 0.138 mmol) in DMF (1385 μL) was addedNaN₃ (45 mg, 0.692 mmol) and NH₄Cl (44.4 mg, 0.831 mmol). The mixturewas stirred at 90° C. overnight. The mixture was cooled to rt andpurified by reverse phase HPLC to isolate the desired product (64 mg,68%) as a yellow solid. MS(ESI) m/z: 448.2 (M+H)⁺.

Example 198.1-(3-Chloro-2-fluorophenyl)-5-methyl-N-[(145)-9-oxo-4-(2H-1,2,3,4-tetrazol-5-yl)-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-1H-pyrazole-4-carboxamide,TFA salt: Example 198 was made in the same way as Example 2 by replacing2J with 198B and using Intermediate 25 in the final step. ¹H NMR (400MHz, MeOD) δ 8.84 (d, J=6.0 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.31 (s,1H), 8.24 (dd, J=8.2, 1.6 Hz, 1H), 8.15 (s, 1H), 7.94 (dd, J=6.0, 1.6Hz, 1H), 7.72 (ddd, J=8.2, 6.6, 1.6 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H),7.49-7.43 (m, 1H), 7.42-7.35 (m, 1H), 5.26 (dd, J=11.0, 6.0 Hz, 1H),2.61-2.51 (m, 1H), 2.35 (s, 3H), 2.29-2.16 (m, 1H), 2.05-1.93 (m, 2H),1.91-1.64 (m, 2H), 1.52-1.37 (m, 1H), 0.85-0.69 (m, 1H) ppm. MS(ESI)m/z: 586.2 (M+H)⁺. Analytical HPLC RT=6.14 min (Method A).

Example 199 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-17-methoxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-5-yl]carbamate,TFA salt

199A. MethylN-(4-{2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-6-methoxypyridin-4-yl}-3-nitrophenyl)carbamate:To a stirred solution of 29G (3.0 g, 6.54 mmol; enriched by chiral SFCseparation method similar to those used for 29H) in chloroform (131 mL)under an argon atmosphere was added silver (I) carbonate (50% onCELITE®) (3.61 g, 6.54 mmol) and iodomethane (1.22 mL, 19.63 mmol),respectively. The reaction mixture was heated at 65° C. After stirringfor 14 hours, the reaction was filtered, concentrated, and purified bynormal phase chromatography to give 199A (2.69 grams, 87%) as a tansolid. MS(ESI) m/z: 473 (M+H)⁺.

199B. MethylN-(3-amino-4-{2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-6-methoxy-pyridin-4-yl}phenyl)carbamate:199A (2.69 g, 5.69 mmol) in MeOH (60 ml) was treated with zinc powder(3.86 g, 59.0 mmol) and ammonium chloride (0.632 g, 11.81 mmol) andheated at 65° C. overnight. The suspension was filtered hot through aplug of CELITE® and concentrated. This residue was re-dissolved in EtOAc(with 10% MeOH), washed with saturated sodium bicarbonate solution,brine, dried over sodium sulfate, filtered, and concentrated to give199B. MS(ESI) m/z: 443 (M+H)⁺.

199C. MethylN-(4-{2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-6-methoxypyridin-4-yl}-3-(2-methylbut-3-enamido)phenyl)carbamate:DIPEA (3.02 mL, 17.29 mmol) was added to a solution of2-methylbut-3-enoic acid (0.865 g, 8.64 mmol) and 199B (2.55 g, 5.76mmol) in EtOAc (57.6 ml) at −10° C. under argon. Next,1-propanephosphonic acid cyclic anhydride (6.79 ml, 11.53 mmol; 50%solution in EtOAc) was added dropwise and the reaction stirred for 1 hunder set conditions and then allowed to come to rt. After 48 hours, thereaction was diluted with EtOAc, washed with saturated NaHCO₃, brine,dried over Na₂SO₄, filtered, and concentrated. Purification by normalphase chromatography gave 199C (2.52 g, 83%) as a white solid. MS(ESI)m/z: 525.1 (M+H)⁺.

199D. tert-ButylN-[(14S)-17-methoxy-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl]carbamate:A solution of 199C (1.50 g, 2.86 mmol) and Ts-OH (0.598 g, 3.15 mmol) inDCM (337 mL) was heated for 0.5 h. The solution was cooled down to roomtemperature and bubbled with argon for 0.5 h. To the solution was addedtricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride(0.728 g, 0.858 mmol) and the resulting solution bubbled with argon foradditional 0.5 h before heating at 45° C. for 12 hours. The reactionmixture was washed with aqueous saturated NaHCO₃ solution. Aqueous layerwas further extracted with DCM (2×30 mL). The combined organic extractwas dried over Na₂SO₄, concentrated, and purified by normal phasechromatography. The olefin double bond was reduced by dissolution inEtOH (50 mL), treatment with platinum oxide (0.065 gram, 0.286 mmol),and subjected to a hydrogen atmosphere (55 psi) overnight. The catalystwas filtered off through a plug of CELITE® and the filtrate concentratedto give 199D (720 mg, 51%) as a diastereomer mixture.

199E1. tert-ButylN-[(10S,14S)-17-methoxy-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl]carbamateand 199E2. tert-butylN-[(10R,14S)-17-methoxy-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo-[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl]carbamate:Diastereomeric mixture 199D (720 mg, 1.44 mmol) was subjected to chiralSFC separation using chiral AD-H 30×250 mm column, with a mixture of 30%EtOH and 70% CO₂ with a flow rate of 85 mL/min and 100 bar at 40° C.Peak 1 was designated as enantiomer A (199E1; 280 mg, 74%) and peak 2was designated as enantiomer B (199E2; 360 mg, 100%). MS(ESI) m/z: 499.1(M+H)⁺ for both enantiomers.

Example 199. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-17-methoxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-5-yl]carbamate,TFA salt: 199E2 (0.020 g, 0.040 mmol) in MeOH (0.20 mL) was treated withHCl (0.501 mL, 2.006 mmol) for 1 hour and then concentrated to dryness.The crude residue was purified reverse phase preparative HPLC. The amineTFA salt was dissolved in DMF (1 mL) then Intermediate 21 (0.012 g,0.048 mmol), EDC (0.015 g, 0.080 mmol), 1-hydroxybenzotriazole hydrate(0.012 g, 0.080 mmol), and DIPEA (0.070 mL, 0.401 mmol), addedrespectively. After 3 hours, reaction mixture was purified by reversephase HPLC to give the desired product (11 mg, 35%) as a white solid.Chirality was assigned based on previous compounds. ¹H NMR (500 MHz,MeOD) δ 7.87-7.84 (m, 1H), 7.64-7.60 (m, 1H), 7.52-7.46 (m, 4H), 7.19(d, J=1.1 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 5.25 (dd, J=10.5, 5.5 Hz,1H), 4.07 (s, 3H), 3.80 (s, 3H), 2.75-2.72 (m, 1H), 2.54 (d, J=0.8 Hz,3H), 2.17-2.12 (m, 1H), 1.98-1.93 (m, 1H), 1.85-1.79 (m, 1H), 1.51-1.45(m, 2H), 1.01 (d, J=7.2 Hz, 3H), 0.64 (m, 1H) ppm. MS(ESI) m/z: 636(M+H)⁺. Analytical HPLC RT=7.32 min (Method B).

Example 200 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-17-ethoxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-5-yl]carbamate,TFA salt

Example 200. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-17-ethoxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19),16-hexaen-5-yl]carbamate,TFA salt: Example 200 was prepared in a similar manner as Example 199 byreplacing iodomethane with iodoethane in the o-alkylation step.Chirality was assigned based on previous compounds. ¹H NMR (500 MHz,DMSO-d₆) δ 9.89 (s, 1H), 9.68 (s, 1H), 8.43 (d, J=8.0 Hz, 1H), 7.95(ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.75 (ddd, J=8.1, 6.6, 1.5 Hz, 1H), 7.53(td, J=8.3, 1.4 Hz, 1H), 7.51-7.47 (m, 1H), 7.46-7.42 (m, 1H), 7.35 (d,J=1.7 Hz, 1H), 7.16 (d, J=0.8 Hz, 1H), 6.66 (d, J=1.1 Hz, 1H), 5.19-5.05(m, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 2.69-2.63 (m, 1H),2.49-2.43 (m, 3H), 2.00-1.83 (m, 2H), 1.77-1.65 (m, 1H), 1.43-1.35 (m,4H), 1.33-1.23 (m, 1H), 0.85 (d, J=6.9 Hz, 3H), 0.37 (d, J=11.0 Hz, 1H)ppm. MS(ESI) m/z: 650 (M+H)⁺. Analytical HPLC RT=7.58 min (Method B).

Example 201 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10,16-dimethyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19)-pentaen-5-yl]carbamate

201A. MethylN-(4-{6-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}-3-nitrophenyl)carbamate:To a stirred solution of 29G (1.0 g, 2.181 mmol; enriched by SFCseparation method similar to that used for 29H) in chloroform (43.6 mL)under an argon atmosphere was added Cs₂CO₃ (0.711 g, 2.181 mmol) andiodomethane (0.929 g, 6.54 mmol). The reaction mixture was heated at 65°C. After 14 hours, the reaction shows a 1:1 ratio of the desiredN-methylated product (more polar by LC) and the O-methoxy (less polar byLC). The reaction mixture was filtered, concentrated, and purified bynormal phase column chromatography. Both products were isolated withdesired product (0.542 g, 53%) being carried forward to subsequentreaction and the O-methylated side-product (382 mg, 37%, analytical datacorresponds that from an earlier alternative synthesis) being set aside.MS(ESI) m/z: 473 (M+H)⁺.

201B. MethylN-(4-{6-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-1-methyl-2-oxo-1,2-dihydropyridin-4-yl}-3-(2-methylbut-3-enamido)phenyl)carbamate:Ammonium chloride (0.122 g, 2.286 mmol) was added to a suspension of201A (0.540 g, 1.143 mmol) and zinc (0.747 g, 11.43 mmol) in MeOH (11.43mL). The reaction mixture was heated at 65° C. overnight. The reactionmixture was through a plug of CELITE® and concentrated. This residue wasre-dissolved in EtOAc, washed with saturated sodium bicarbonatesolution, brine, dried over sodium sulfate, filtered, and concentrated.1-Propanephosphonic acid cyclic anhydride (1.455 g, 2.286 mmol; 50% inEtOAc) was added to a solution of aniline intermediate,2-methylbut-3-enoic acid (0.460 g, 4.58 mmol), and DIPEA (1.2 ml, 6.86mmol) in EtOAc (30 mL). After stirring for 48 hours, the reactionmixture was washed with saturated sodium bicarbonate solution, brine,dried over sodium sulfate, filtered, and concentrated to give thedesired product. MS(ESI) m/z: 525.2 (M+H)⁺.

201C. tert-ButylN-[(145)-5-[(methoxycarbonyl)amino]-10,16-dimethyl-9,17-dioxo-8,16-diazatricyclo-[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19)-pentaen-14-yl]carbamate:201B (200 mg, 0.381 mmol) dissolved in DCE (anhydrous) (21.8 mL) wascharged to two large microwave vials in equal portions. After degassingfor 15 min,tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride(130 mg, 0.152 mmol) was added in equal portions to each vial followedby irradiation at 120° C. for 30 min under microwave conditions. Thereaction mixture was concentrated and purified by reverse phasepreparative HPLC. The diastereomers were successfully separated underthese conditions. Peak 1 was designated as Diastereomer A (201C1; minor;more polar RT by ACN prep.) and Peak 2 was designated as Diastereomer B(201C2, major; less polar RT by ACN prep). Each diastereomer wasdissolved in EtOH (10 mL), treated with platinum(IV) oxide (13 mg, 0.057mmol), and subjected to hydrogen gas (55 psi) overnight. The reactionswere filtered, concentrated. 201C1 (42 mg, 44%) was set aside and 201C2(51 mg, 54%) was carried forward to the next reaction without furtherpurification. MS(ESI) m/z: 499 (M+H)⁺ for both diastereomers.

Example 201. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10,16-dimethyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(18),2,4,6,15(19)-pentaen-5-yl]carbamate:201C2 (0.022 g, 0.044 mmol) in MeOH (0.200 mL) was treated with HCl(0.552 ml, 2.206 mmol) for 1 hour and then concentrated to dryness. Theamine HCl salt was dissolved in DMF (1 mL) then Intermediate 21 (0.014g, 0.053 mmol), EDC (0.017 g, 0.088 mmol), 1-hydroxybenzotriazolehydrate (0.014 g, 0.088 mmol), DIPEA (0.077 ml, 0.441 mmol), addedrespectively. After 15 hours, the reaction mixture was purified byreverse phase preparative HPLC to give the desired product (10 mg, 33%)as a white solid. Chirality was assigned based on previous compounds. ¹HNMR (500 MHz, MeOD) δ 7.83 (ddd, J=8.2, 6.8, 1.5 Hz, 1H), 7.57 (ddd,J=8.0, 6.5, 1.7 Hz, 1H), 7.53-7.45 (m, 4H), 6.74 (d, J=1.7 Hz, 1H), 6.60(d, J=1.9 Hz, 1H), 5.26 (dd, J=11.0, 4.4 Hz, 1H), 3.77 (s, 3H), 3.66 (s,3H), 2.58-2.53 (m, 1H), 2.52-2.49 (m, 3H), 2.19-2.14 (m, 1H), 2.11-2.06(m, 1H), 1.67-1.61 (m, 2H), 1.46-1.40 (m, 1H), 1.35-1.29 (m, 1H), 1.19(d, J=6.9 Hz, 3H) ppm. MS(ESI) m/z: 636 (M+H)⁺. Analytical HPLC RT=6.28min (Method B).

Example 202 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 202. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16,17-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: Example 202 was made in the same way as Example 22 by using22IA and replacing Intermediate 2 with Intermediate 21. ¹H NMR (400 MHz,CDCl₃) δ 9.63 (br. s., 1H), 8.74-8.11 (m, 2H), 8.04-7.31 (m, 4H),7.21-6.97 (m, 1H), 5.53 (br. s., 1H), 3.64-3.32 (m, 3H), 2.76 (br. s.,1H), 2.57-2.37 (s, 3H), 2.27 (br. s., 1H), 2.09 (d, J=9.3 Hz, 1H),1.99-1.48 (m, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.43 (br. s., 1H) ppm.MS(ESI) m/z: 607.2 (M+H)⁺. Analytical HPLC RT=9.17 min (Method A).

Example 203 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10,10-difluoro-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

Example 203. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10,10-difluoro-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 203 was made in the same way as example 34 byreplacing 2-methylbut-3-enoic acid with 2,2-difluoropent-4-enoic acid instep 21 and using Intermediate 25 in the final step. ¹H NMR (400 MHz,MeOD) δ 9.69 (s, 1H), 8.28 (s, 1H), 7.73 (ddd, J=8.2, 6.6, 1.6 Hz, 1H),7.65 (d, J=1.6 Hz, 1H), 7.60-7.44 (m, 4H), 7.43-7.35 (m, 1H), 5.23 (dd,J=10.4, 6.6 Hz, 1H), 3.77 (s, 3H), 2.45-2.29 (m, 4H), 2.20-2.04 (m, 3H),1.63 (br. s., 1H), 1.05 (br. s., 1H) ppm. MS(ESI) m/z: 616.2 (M+H)⁺.Analytical HPLC RT=6.89 min (Method A).

Example 204 Methyl N-[(15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-8,17,19-triazatetracyclo[14.2.1.0^(2,7).0^(11,13)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl]carbamate,TFA salt

204A. tert-ButylN-[(15S)-5-[(methoxycarbonyl)amino]-9-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-8,17,19-triazatetracyclo[14.2.1.0^(2,7).0^(11,13)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl]carbamate:To a mixture of 34F (100 mg, 0.175 mmol) and diacetoxypalladium (1.963mg, 8.75 μmol) in CH₂Cl₂ (20 mL) at 0° C. was added diazomethane (73.5mg, 1.749 mmol) dropwise. The reaction was stirred for 2 h and quenchedwith 1 mL HOAc. The solution was neutralized with aq. Na₂CO₃ andextracted with ether. The organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified byreverse phase HPLC yield the product (29 mg, 28%) as white solid. NMRwas shown to be a mixture a diastereomers. MS(ESI) m/z: 586.4 (M+H)⁺.

Example 204. MethylN-[(15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-8,17,19-triazatetracyclo[14.2.1.0^(2,7).0^(11,13)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl]carbamate,TFA salt: Example 204 was made in the same way as Example 34 byreplacing 34F with 204A. Example 204 was a mixture of diastereomers. ¹HNMR (500 MHz, MeOD) δ 8.36 (s, 1H), 7.74 (ddd, J=8.3, 6.7, 1.8 Hz, 1H),7.60 (d, J=1.7 Hz, 1H), 7.52-7.37 (m, 5H), 5.31 (dd, J=4.4, 3.6 Hz, 1H),3.78 (s, 3H), 2.80-2.70 (m, 2H), 2.38 (d, J=0.8 Hz, 3H), 1.58-1.46 (m,2H), 1.06 (tt, J=9.3, 4.7 Hz, 1H), 0.82 (ddd, J=11.1, 7.6, 3.9 Hz, 1H),0.60-0.48 (m, 2H) ppm. MS(ESI) m/z: 592.0 (M+H)⁺. Analytical HPLCRT=5.31 min (Method A).

Example 205 MethylN-[(12E,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate,TFA salt

Example 205. MethylN-[(12E,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate,TFA salt: Example 205 was made in the same way as Example 58 byreplacing Intermediate 22 with Intermediate 25. ¹H NMR (500 MHz, MeOD) δ8.30 (s, 1H), 7.72 (ddd, J=8.3, 6.8, 1.7 Hz, 1H), 7.58 (s, 1H),7.50-7.37 (m, 6H), 5.60 (ddd, J=15.2, 9.1, 5.6 Hz, 1H), 5.48-5.40 (m,1H), 5.20 (dd, J=10.5, 4.7 Hz, 1H), 3.76 (s, 3H), 2.91-2.85 (m, 1H),2.67-2.60 (m, 1H), 2.55-2.36 (m, 7H) ppm. MS(ESI) m/z: 592.3 (M+H)⁺.Analytical HPLC RT=5.84 min (Method A).

The following Examples in Table 11 were made by using the same procedureas shown in Example 34. The acids used in the final step are asindicated in the below table in the Intermediate section. Variouscoupling reagents could be used other than the one described in Example34 like BOP, PyBop, EDC/HOBt, HATU or T3P. Boc and SEM deprotection wasachieved prior to the final coupling unlike with Example 34 where theBoc group alone was removed in step 34J.

TABLE 11 RT, min Example # Stereochemistry R M + H Method A 206Homochiral

591.3 6.49 207 Homochiral

612.9 5.99 208 Homochiral

601.9 6.25 209 Homochiral

536.1 5.02 210 Homochiral

595.2 4.29 211 Homochiral

635.9 6.70 212 Homochiral

596.0 6.45 213 Homochiral

594.2 5.75 214 Homochiral

561.2 5.08

Example 215 2-MethoxyethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

215A.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-3H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduredescribed in step 34A, by replacing Intermediate 16 with Intermediate18; followed by step 34B. MS(ESI) m/z: 467.1 (M+2+H)⁺.

215B.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a cooled (0° C.) solution of 215A (15 g, 32.2mmol) in THF (77 mL) was added N,N-dicyclohexylmethylamine (7.52 mL,35.5 mmol) followed by the dropwise addition of SEM-Cl (6.29 mL, 35.5mmol). The reaction was stirred at 0° C. for 2 h and then it was allowedto warm slowly to rt. After 18 h, the yellow suspension was diluted withEtOAc, washed with saturated sodium bicarbonate, brine, dried overMgSO₄, filtered and concentrated. Purification by normal phasechromatography gave 12.24 g (64%) of 215B as an off-white solid. MS(ESI)m/z: 595.1 (M+H)⁺ and 597.2 (M+2+H)⁺.

215C.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: A thick-walled vial containing 215B (2 g, 3.36 mmol),copper(I) iodide (0.128 g, 0.672 mmol), L-proline (0.155 g, 1.343 mmol)and potassium carbonate (1.392 g, 10.07 mmol) in DMSO (6.72 mL) wasvacuumed and back-filled with argon three times. Then 28% aq. ammoniumhydroxide (0.607 mL, 4.37 mmol) was added. The vial was sealed with aTeflon-coated screw cap and the reaction was warmed to 85° C. After 20h, the reaction was cooled to rt, diluted with EtOAc, washed with water,brine, dried over sodium sulfate, filtered and concentrated.Purification by normal phase chromatography afforded 1.05 g (58.8%) of215C as a yellow solid. MS(ESI) m/z: 532.5 (M+H)⁺.

215D. tert-ButylN-[(1S)-1-(4-{4-[(methoxycarbonyl)amino]-2-[(2R)-2-methylbut-3-enamido]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-en-1-yl]carbamate:To a cooled (0° C.), clear yellow orange solution of 215C (4.83 g, 9.08mmol) in ethyl acetate (91 mL) was added Intermediate 45 (1.0 g, 9.99mmol) and Hunig's base (6.34 mL, 36.3 mmol). Next, 1-propanephosphonicacid cyclic anhydride (T3P) (50% in EtOAc) (13.38 mL, 22.70 mmol) wasadded dropwise over 20 min. and the reaction was stirred at 0° C. After3 h, the reaction was diluted with EtOAc and washed with sat. NaHCO₃.The aqueous layer was extracted with EtOAc (2×). The organic layers werecombined and washed with brine, dried over sodium sulfate, filtered andconcentrated to give an orange foam. Purification by normal phasechromatography gave 215D (4.53 g, 81%) as a white foam. Proton NMRindicated a 3:1 mixture of diastereomers. MS(ESI) m/z: 614.4 (M+H)⁺.

215E. tert-ButylN-[(10R,11E,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-(17),2,4,6,11,15(18)-hexaen-14-yl]carbamate(Diastereomer A) and 215F. tert-butylN-[(10S,11E,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]carbamate(Diastereomer B): To a solution of 215D (4.40 g, 7.17 mmol) indichloromethane (717 mL) was added pTsOH monohydrate (1.523 g, 7.89mmol) and the mixture was degassed with argon for 30 min. Next, theflask was equipped with a reflux condenser and the reaction was warmedto 40° C. for 1 h. Next, a burgundy solution of Grubbs catalyst 2ndgeneration (2.440 g, 2.87 mmol) in 20 mL of DCM (degassed with argon)was added dropwise via syringe over 35 to 40 min. After 21.5 h, thereaction was cooled to rt. The reaction mixture was washed withsaturated NaHCO₃, brine, dried over MgSO₄, filtered and concentrated togive a brown foam. Purification by normal phase chromatography gave215E, Diastereomer A (1.71 g, 41%) as an off-white solid and a mixtureof 215E, Diastereomer A and 215F, Diastereomer B (1.4 g). MS(ESI) m/z:586.3 (M+H)⁺.

215G. tert-ButylN-[(10R,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]carbamate:A dark brown solution of 215E (1.71 g, 2.92 mmol) in EtOAc (97 mL) wasdegassed with argon for 30 minutes. Next, platinum(IV) oxide (0.066 g,0.292 mmol) was added and hydrogen gas from a balloon was bubbledthrough the reaction mixture for several minutes. The reaction wasstirred under a hydrogen atmosphere. After 24 h, an additional amount ofplatinum(IV) oxide (0.192 g, 0.876 mmol) was added and the reaction wasstirred under a hydrogen atmosphere. After 21 h, the reaction wasstopped. The vessel was purged with vacuum/argon three times, thenCELITE® was added, and the reaction was filtered rinsing with EtOAc. Theresulting clear, yellow brown filtrate was concentrated to give anoff-white solid weighing 1.66 g. Recrystallization from methanol (30 mL)gave 215G (0.575 g, 34%) as a white solid. MS(ESI) m/z: 588.4 (M+H)⁺.

215H. tert-ButylN-[(10R,14S)-5-amino-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]carbamate(Diastereomer A), 2 TFA and 2151. tert-butylN-[(10S,14S)-5-amino-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]carbamate(Diastereomer B), 2 TFA: A sealed tube containing a white suspension of215G (0.100 g, 0.170 mmol) in MeOH (2.84 mL) and 1.0 M NaOH (1.021 mL,1.021 mmol) was warmed to 75° C. After 2.5 h, additional MeOH (5.6 mL)and 1.0 M NaOH (1.021 mL, 1.021 mmol) were added and the reaction washeated at 75° C. After 16.5 h, additional 1.0 M NaOH (2 mL) was addedand the reaction was heated at 75° C. After 21 h, the reaction wasstopped and cooled to rt. The reaction was neutralized with 1.0 N HCland concentrated. The solid was partitioned between EtOAc and saturatedNaHCO₃ and the layers were separated. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated to give a white solidweighing 0.107 g. Purification by reverse phase chromatography gave 215H(Diastereomer A) (0.082 g, 63.6% yield) and 2151 (Diastereomer B) (0.025g, 19%). MS(ESI) m/z: 530.4 (M+H)⁺.

215J. tert-ButylN-[(10R,14S)-5-{[(2-methoxyethoxy)carbonyl]amino}-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]carbamate:To a cooled (0° C.), clear, slightly yellow solution of 215H (0.082 g,0.108 mmol) in dichloromethane (1.082 mL) and pyridine (0.026 mL, 0.325mmol) was added 2-methoxyethyl chloroformate (0.013 mL, 0.114 mmol).After 1.5 h, the reaction was diluted with EtOAc and washed with sat.NaHCO₃, brine, dried over sodium sulfate, filtered and concentrated togive 215J (0.062 g, 91% yield) as an off-white solid. MS(ESI) m/z: 632.4(M+H)⁺. This material was used in the next step without furtherpurification.

215K. 2-MethoxyethylN-[(10R,14S)-14-amino-10-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,2 HCl: A sealed tube containing a clear, slightly yellow solution of215J (0.062 g, 0.098 mmol) in 4.0 M HCl in dioxane (2.453 mL, 9.81 mmol)was heated at 75° C. After 1 h, the resulting suspension wasconcentrated to give 215K (0.057 g, 122%) as a dull, yellow solid.MS(ESI) m/z: 402.1 (M+H)⁺. This material was used in the next stepwithout further purification.

Example 215. 2-MethoxyethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 215 was prepared according to the procedure describedin Example 2, by replacing 2M with 215K and by replacing Intermediate 11with Intermediate 1. ¹H NMR (500 MHz, MeOD) δ 8.91 (d, J=2.2 Hz, 1H),7.84 (ddd, J=8.1, 6.6, 1.5 Hz, 1H), 7.73 (ddd, J=8.3, 6.8, 1.7 Hz, 1H),7.58 (d, J=1.9 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.47-7.40(m, 2H), 5.41 (dd, J=10.3, 6.7 Hz, 1H), 4.32-4.27 (m, 2H), 3.68-3.63 (m,2H), 3.39 (s, 3H), 2.82-2.73 (m, 1H), 2.34-2.24 (m, 1H), 2.18-2.08 (m,1H), 1.82-1.73 (m, 1H), 1.67-1.56 (m, 2H), 1.04 (d, J=7.2 Hz, 3H),0.78-0.65 (m, 1H). MS(ESI) m/z: 625.1 (M+H)⁺. Analytical HPLC RT=4.92min (Method D).

Example 216 MethylN-[(12E,15S)-18-chloro-15-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate,TFA salt

216A. tert-ButylN-[(12E,15S)-18-chloro-5-[(methoxycarbonyl)amino]-9-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl]carbamate:A white suspension of 57F (2.56 g, 4.37 mmol) and NCS (0.700 g, 5.24mmol) in CHCl₃ (18.36 mL) and ACN (18.36 mL) was heated to 65° C. After10 h, the reaction mixture was cooled to rt and partitioned between DCMand water and the layers were separated. The aqueous layer was extractedwith DCM (2×). The organic layers were combined, washed with saturatedNaHCO₃, brine, dried over MgSO₄, filtered and concentrated to give abrown foam. The E- and Z-alkene isomers were separated by reverse phasechromatography. The fractions containing the E-alkene isomer werecombined, neutralized with a solution of saturated NaHCO₃, and thenconcentrated to give a solid. The solid was partitioned between EtOAcand water and the layers were separated. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thedesired product (1.15 g, 42%) as yellow foam. MS(ESI) m/z: 620.1 (M+H)⁺.

216B. MethylN-[(12E,15S)-15-amino-18-chloro-9-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate:To a solution of 216A (0.24 g, 0.387 mmol) in DCM (5 mL) was added TFA(1 mL, 12.98 mmol). The reaction was stirred at rt for 1 h andconcentrated. Purification by reverse phase chromatography gave, afterneutralization of the fractions with saturated NaHCO₃ and concentration,a solid. The solid was partitioned between EtOAc and water and thelayers were separated. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated to give the desired product(0.095 g, 47%) as a white solid. MS(ESI) m/z: 520.1 (M+H)⁺.

Example 216. MethylN-[(12E,15S)-18-chloro-15-[1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-amido]-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate,TFA salt: Example 216 was made in the same way as Example 57 by using216B and Intermediate 1. ¹H NMR (400 MHz, MeOD) δ 9.52 (br. s., 1H),8.84 (dd, J=17.0, 2.2 Hz, 2H), 7.75 (td, J=7.3, 1.4 Hz, 1H), 7.68 (m,1H), 7.41 (m, 1H), 7.35-7.31 (m, 2H), 5.27 (dd, J=10.7, 6.3 Hz, 1H),4.51-4.20 (m, 1H), 3.67 (s, 3H), 2.51-2.33 (m, 1H), 2.30-1.92 (m, 2H),1.67-1.42 (m, 2H), 1.45-1.07 (m, 2H), 0.93 (s, 1H) ppm. MS(ESI) m/z:613.0 (M+H)⁺. Analytical HPLC RT=8.53 min (Method A).

Example 217 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-11-oxa-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

217A. (S)-1-(4-Chloropyridin-2-yl)but-3-en-1-amine: To (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (3 g, 10.61 mmol) wasadded HCl in dioxane (15 mL, 60.0 mmol) and the reaction was stirred atroom temperature for 1 h. The reaction mixture was then concentrated andtaken to the next step without further purification. MS(ESI) m/z: 183.1(M+H)⁺.

217B. (S)-Benzyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate: To asolution of 217A (1.938 g, 10.61 mmol) in MeOH (40 mL) was added benzyl(2,5-dioxopyrrolidin-1-yl) carbonate (2.64 g, 10.61 mmol) followed byDIEA (3.71 mL, 21.22 mmol) and the reaction was stirred at roomtemperature over night. The mixture was concentrated. The residue wasdiluted with ethylacetate and washed with brine. The organic layer wasdried over MgSO₄ and concentrated. The crude product was purified bysilica gel chromatography to yield the desired product (3.3 g, 95%) as ayellow solid. MS(ESI) m/z: 317.0 (M+H)⁺.

217C. (S)-Benzyl (1-(4-chloropyridin-2-yl)-3-oxopropyl)carbamate:(Reference: J. Org. Chem., 58(4):860-866 (1993)) To a solution of 217B(1 g, 3.16 mmol) in MeOH (40 mL) and water (20 mL) was added OsO₄ 4 wt %in water (1.350 mL, 0.221 mmol). After 5 min of stirring, a clear tanyellow solution formed. To this solution was then added sodium periodate(2.026 g, 9.47 mmol) with vigorous stirring. The color discharged thengradually a white suspension formed. The reaction mixture was continuedto stir at room temperature over night. The reaction mixture was dilutedwith water (˜100 mL) and extracted with EtOAc (3×). The combined organiclayers were dried over MgSO₄, filtered, and concentrated. The residuewas purified by silica gel chromatography to yield the desired product(66%). MS(ESI) m/z: 319.0 (M+H)⁺.

217D. (S)-Benzyl (1-(4-chloropyridin-2-yl)-3-hydroxypropyl)carbamate: Toa solution of 217C (2.2 g, 6.90 mmol) in ethanol (50 mL) was addedsodium borohydride (0.522 g, 13.80 mmol) and the reaction was stirred atrt over night. The reaction mixture was then quenched with brine andextracted with EtOAc. The organic layer was concentrated and the residuewas purified by silica gel chromatography to yield the desired product(1.58 g, 68%). MS(ESI) m/z: 321.0 (M+H)⁺.

217E. (S)-tert-Butyl2-(3-(((benzyloxy)carbonyl)amino)-3-(4-chloropyridin-2-yl)propoxy)acetate:To a mixture of tert-butyl bromoacetate (0.415 mL, 2.81 mmol) and NaH(224 mg, 5.61 mmol) in THF (18 mL) at 0° C. was added a solution of 217D(900 mg, 2.81 mmol) in THF (9 mL) dropwise. The reaction mixture wasstirred at 0° C. for additional 1 h and then quenched with saturatedNH₄Cl. The mixture was extracted with ethylacetate. The organic layerwas dried over MgSO₄ and concentrated. The residue was purified bysilica gel chromatography to isolate the desired product (300 mg, 23%).MS(ESI) m/z: 435.0 (M+H)⁺.

217F. (S)-tert-Butyl2-(3-(4-(2-amino-4-nitrophenyl)pyridin-2-yl)-3-(((benzyloxy)carbonyl)amino)propoxy)acetate:Argon was bubbled through a solution of DMSO (8 mL) and water (0.062 mL,3.45 mmol) for 30 min. Then this solvent mixture was added to amicrowave vial containing 217E (300 mg, 0.690 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitroaniline (345 mg, 1.380mmol) and phosphoric acid, potassium salt (293 mg, 1.380 mmol). Argonwas again bubbled through the deep red solution for 15-20 min. Then1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, DCM (56.7mg, 0.069 mmol) was added and the mixture was stirred at 90° C. for 5 h.The reaction mixture was diluted with ethyl acetate and washed withbrine. The organic layer was dried over MgSO₄ and concentrated. Theresidue purified by silica gel chromatography to yield the desiredproduct (170 mg, 43%). MS(ESI) m/z: 537.0 (M+H)⁺.

217G. (S)-tert-Butyl2-(3-(((benzyloxy)carbonyl)amino)-3-(4-(2,4-diaminophenyl)pyridin-2-yl)propoxy)acetate:To a solution of 217F (170 mg, 0.317 mmol) in MeOH (8 mL) was added zinc(207 mg, 3.17 mmol) and ammonium chloride (169 mg, 3.17 mmol). Thereaction was stirred at rt for 5 h. The reaction mixture was filteredusing a 0.45 micron filter and concentrated to give the crude productwhich was purified by silica gel chromatography to yield the desiredproduct (70 mg, 41%). MS(ESI) m/z: 507.0 (M+H)⁺.

217H. (S)-tert-Butyl2-(3-(4-(2-amino-4-((methoxycarbonyl)amino)phenyl)pyridin-2-yl)-3-(((benzyloxy)carbonyl)amino)propoxy)acetate:To a solution of 217G (70 mg, 0.138 mmol) in DCM (5 mL) at −78° C. wasadded pyridine (0.011 mL, 0.138 mmol) followed by methyl chloroformate(10.70 μL, 0.138 mmol). The reaction was stirred at −78° C. for 1 h andthen quenched with saturated ammonium chloride. The mixture wasextracted with DCM and EtOAc. The combined organic layer wasconcentrated and purified by silica gel chromatography to yield thedesired product (70 mg, 85%). MS(ESI) m/z: 565.1 (M+H)⁺.

217I.(S)-2-(3-(4-(2-Amino-4-((methoxycarbonyl)amino)phenyl)pyridin-2-yl)-3-(((benzyloxy)carbonyl)amino)propoxy)aceticacid: 217H (70 mg, 0.124 mmol) was treated with HCl in dioxane (5 mL,20.00 mmol) at rt under argon for 1 h. The reaction mixture was thenconcentrated and the crude product was taken to the next step withoutfurther purification (56 mg, 84%). MS(ESI) m/z: 509.0 (M+H)⁺.

217J. BenzylN-[(14S)-5-[(methoxycarbonyl)amino]-9-oxo-11-oxa-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl]carbamate:To a round bottom flask was added BOP (41.3 mg, 0.093 mmol), DMAP (19.17mg, 0.157 mmol) and DIEA (0.046 mL, 0.262 mmol) and DCM (11 mL). Theabove mixture was kept stirring at room temperature while in a separateround bottom containing 2171 (19 mg, 0.037 mmol) was added DIEA (0.046mL, 0.262 mmol) and DMF (2 mL). The DMF solution was then added to theDCM solution dropwise over a period of 6 h. The reaction wasconcentrated and the crude product was then purified by reverse phaseHPLC to yield the desired product (5.2 mg, 27%). MS(ESI) m/z: 491.0(M+H)⁺.

217K. MethylN-[(14S)-14-amino-9-oxo-11-oxa-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate:To a degassed solution of 217J (1.2 mg, 2.446 μmol) in ethanol (1 mL)was added Pd/C (2.60 mg, 2.446 μmol). The reaction vessel was purgedwith hydrogen 3 times and then allowed to stir under hydrogen balloonfor 2 h. The reaction mixture was filtered through CELITE® eluting withMeOH. The filtrated was concentrated to yield the desired product (0.9mg, 98%). MS(ESI) m/z: 357.2 (M+H)⁺.

Example 217. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-11-oxa-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: To a solution of Intermediate 25 (2.59 mg, 10.19 μmol) in DMF(0.5 mL) was added EDC (3.55 mg, 0.019 mmol), HOBT (4.5 mg, 0.019 mmol)and DIEA (0.016 mL, 0.093 mmol). The reaction was stirred at rt for 15min and added 217K (3.3 mg, 9.26 μmol). The reaction was stirred at rtunder argon over night. The reaction mixture was concentrated andpurified by reverse phase HPLC to yield the desired product. ¹H NMR (500 MHz, acetonitrile-d₃) δ 8.65 (d, J=5.8 Hz, 1H), 8.60 (s, 1H),8.20-8.13 (m, 3H), 8.05 (s, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.72-7.64 (m,2H), 7.61 (d, J=8.5 Hz, 1H), 7.48 (dd, J=8.5, 1.9 Hz, 1H), 7.45-7.39 (m,1H), 7.37-7.31 (m, 1H), 5.41-5.29 (m, 1H), 4.00 (d, J=12.9 Hz, 1H), 3.77(s, 1H), 3.68-3.58 (m, 1H), 3.37-3.25 (m, 2H), 2.51-2.38 (m, 3H), 2.36(s, 3H), 2.25-2.18 (m, 1H) ppm. MS(ESI) m/z: 593.0 (M+H)⁺. AnalyticalHPLC RT=6.18 min (Method A).

Example 218 MethylN-[(14R)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-12-oxa-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt

218A. tert-ButylN-[(1R)-1-(4-{2-amino-4-[(methoxycarbonyl)amino]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-(benzyloxy)ethyl]carbamate:This compound was prepared following the literature procedure (WO11/100401, Example 10, by replacing(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanoic acid. Yellowsolid. MS(ESI) m/z: 612.5 (M+H)⁺.

218B. tert-ButylN-[(1R)-2-(benzyloxy)-1-(4-{4-[(methoxycarbonyl)amino]-2-(trifluoroacetamido)phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)ethyl]carbamate:To a solution of 218A (2.035 g, 3.33 mmol) in DCM (107 mL) at 0° C. wasadded pyridine (0.404 mL, 4.99 mmol), followed by TFAA (0.611 mL, 4.32mmol). After 30 min, the reaction was stopped and it was washed withsaturated NaHCO₃, 1 N HCl, brine, dried over magnesium sulfate, filteredand concentrated to give the desired product (2.3 g, 98% yield) as ayellow solid. The material was carried onto the next step withoutfurther purification.

218C. tert-ButylN-[(1R)-2-hydroxy-1-(4-{4-[(methoxycarbonyl)amino]-2-(trifluoroacetamido)phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)ethyl]carbamate:To the solution of 218B (2.07 g, 2.92 mmol) in EtOH (58.5 mL) was addedTFA (0.338 mL, 4.39 mmol). The reaction was stirred at rt for 5 min,then 10% palladium on carbon (0.311 g, 0.292 mmol) was added. Hydrogenwas bubbled in for a few minutes, and the reaction was then stirredunder a hydrogen balloon for 24 h. The reaction was filtered through a45 μm GMF filter, rinsing with MeOH. The filtrate was concentrated. Theresidue was dissolved in EtOAc, washed with saturated NaHCO₃, brine,dried over Na₂SO₄, filtered and concentrated. Purification by silica gelchromatography afforded the desired product (1.61 g, 89%) as a whitesolid. MS(ESI) m/z: 618.4 (M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 8.58 (d,J=2.2 Hz, 1H), 7.68-7.62 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 5.58 (d,J=10.7 Hz, 1H), 5.46 (d, J=11.0 Hz, 1H), 5.04 (t, J=6.2 Hz, 1H), 3.92(d, J=6.6 Hz, 2H), 3.77 (s, 3H), 3.65 (t, J=8.1 Hz, 2H), 1.46 (s, 9H),1.04-0.92 (m, 2H), 0.02 (s, 9H) ppm.

218D. Benzyl3-[(2R)-2-{[(tert-butoxy)carbonyl]amino}-2-(4-{4-[(methoxycarbonyl)amino]-2-(trifluoroacetamido)phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)ethoxy]propanoate,TFA salt: To the solution of 218C (0.054 g, 0.074 mmol), benzyl acrylate(0.575 mL, 3.69 mmol) in THF (0.922 mL) at rt was addedbenzyltrimethylammonium hydroxide (0.087 mL, 0.221 mmol) (40 wt % inwater). The reaction was stirred at rt for 3 days, then it wasconcentrated. Purification by reverse phase HPLC afforded the desiredproduct (0.013 g, 20%) as a white solid. MS(ESI) m/z: 780.4 (M+H)⁺. ¹HNMR (500 MHz, MeOD) δ 8.26 (br. s., 1H), 7.61-7.55 (m, 3H), 7.47 (d,J=7.4 Hz, 1H), 7.34-7.23 (m, 4H), 5.57-5.44 (m, 2H), 5.20-5.15 (m, 1H),5.08-4.98 (m, 2H), 3.88-3.73 (m, 7H), 3.64 (t, J=8.3 Hz, 2H), 2.61 (t,J=5.9 Hz, 2H), 1.43 (s, 9H), 1.04-0.90 (m, 2H), 0.01 (s, 9H) ppm.

218E.3-[(2R)-2-(4-{2-Amino-4-[(methoxycarbonyl)amino]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-{[(ten-butoxy)carbonyl]amino}ethoxy]propanoicacid, 2 TFA salt: To the solution of 218D (0.013 g, 0.015 mmol) in MeOH(1 mL) was added 1 N NaOH (0.1 mL, 0.100 mmol). The reaction was stirredat 75° C. in a sealed tube. After 7 h, the reaction was cooled to rt andthen it was concentrated. Purification by reverse phase HPLC affordedthe desired product (0.008 g, 67%) as a yellow solid. MS(ESI) m/z: 594.4(M+H)⁺.

218F. tert-ButylN-[(14R)-5-[(methoxycarbonyl)amino]-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-12-oxa-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]carbamate,TFA salt: To the solution of 218E (0.008 g, 9.73 μmol) in DMF (9.73 mL)was added BOP (0.015 g, 0.034 mmol), DMAP (4.16 mg, 0.034 mmol), andDIPEA (8.50 μL, 0.049 mmol). The reaction was stirred at rt for 16 h andthen it was concentrated. Purification by reverse phase HPLC affordedthe desired product (0.005 g, 75%) as a yellow solid. MS(ESI) m/z: 576.3(M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 7.67 (s, 1H), 7.61 (d, J=1.9 Hz, 1H),7.53 (d, J=8.5 Hz, 1H), 7.41 (dd, J=8.4, 2.1 Hz, 1H), 5.79 (d, J=11.0Hz, 1H), 5.59 (d, J=11.0 Hz, 1H), 5.19 (t, J=2.6 Hz, 1H), 4.15 (dd,J=10.5, 2.5 Hz, 1H), 3.99 (dt, J=8.7, 3.5 Hz, 1H), 3.81-3.69 (m, 5H),3.56-3.48 (m, 1H), 3.42 (dd, J=10.2, 3.0 Hz, 1H), 2.71 (ddd, J=14.5,11.2, 3.7 Hz, 1H), 2.35 (dt, J=14.3, 2.8 Hz, 1H), 1.43 (s, 9H),1.13-0.96 (m, 2H), 0.06 (s, 9H) ppm.

218G. MethylN-[(14R)-14-amino-9-oxo-12-oxa-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,2 HCl salt: The solution of 218F (0.005 g, 7.25 μmol) in 4 M HCl in1,4-dioxane (0.5 mL, 2.000 mmol) in a sealed vial was heated at 65° C.After 1 h, the reaction was cooled to rt and then it was concentrated togive the desired product (3 mg, 100% yield) as a yellow solid. MS(ESI)m/z: 346.2 (M+H)⁺. The material was carried onto the next step withoutfurther purification.

Example 218. MethylN-[(14R)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-12-oxa-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate,TFA salt: Example 218 (0.0021 g, 41% yield, white solid) was preparedaccording to the procedures described in Example 2 by replacing 2M with218G and by replacing Intermediate 11 with Intermediate 25. MS(ESI) m/z:582.2 (M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 8.30 (s, 1H), 7.75 (ddd, J=8.3,6.8, 1.7 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H),7.51-7.47 (m, 2H), 7.44-7.39 (m, 2H), 5.34 (dd, J=7.2, 4.4 Hz, 1H),3.96-3.85 (m, 2H), 3.84-3.77 (m, 5H), 2.67-2.61 (m, 1H), 2.55 (ddd,J=14.4, 6.3, 3.2 Hz, 1H), 2.42 (d, J=0.8 Hz, 3H) ppm. Analytical HPLCRT=5.54 min (Method A).

Example 219 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-10-oxa-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt

219A. tert-ButylN-[(1S)-1-(4-{2-amino-4-[(methoxycarbonyl)amino]phenyl}pyridin-2-yl)-4-hydroxybutyl]carbamate:To a solution of 2H (0.110 g, 0.267 mmol) in THF (5 mL) was added 1.0 Mborane in THF (0.533 mL, 0.533 mmol). After 3 h, the reaction mixturewas cooled with an ice bath. Next, 6 N NaOH (0.089 mL, 0.533 mmol) wasslowly added followed by slow addition of H₂O₂ (0.054 mL, 0.533 mmol).The reaction was allowed to warm to rt. After 1 h, the reaction wasextracted with ethyl acetate (20 mL). The organic layer was washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give apale yellow oil. Purification by normal phase chromatography gave thedesired product (0.150 g, 27%) as a pale yellow semi-solid. MS(ESI) m/z:431.2 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ 8.49-8.50 (m, 1H), 7.51 (s, 1H),7.40 (d, J=5.02 Hz, 1H), 7.00-7.14 (m, 2H), 6.83 (dd, J=8.41, 2.13 Hz,1H), 4.68 (br. s, 1H), 3.75 (s, 3H), 3.54-3.64 (m, 2H), 1.51-2.05 (m,5H), 1.44 (s, 9H).

219B. To a cooled (0° C.) solution of 219A (0.050 g, 0.116 mol) in DCM(10 mL) and acetonitrile (10 mL) was added phosgene (20% toluene) (0.077mL, 0.139 mmol). The reaction mixture was allowed to warm to rt. After 1h, the reaction was concentrated by purging with nitrogen to give aresidue. In a separate flask, a solution of TEA (0.113 mL, 0.813 mmol)and DMAP (0.004 g, 0.116 μmol) in DCM (25 mL) was prepared. The aboveresidue was dissolved in DCM (10 mL) and this solution was slowly addedover 2 h using a syringe pump to the TEA/DMAP solution. The reaction wasconcentrated. Purification by silica gel chromatography provided thedesired product (0.03 g 57%) as an off white solid. MS(ESI) m/z: 457.2(M+H)⁺. ¹H NMR (300 MHz, MeOD) δ 8.51 (d, J=5.6 Hz, 1H), 7.73 (s, 1H),7.56-7.59 (m, 1H), 7.18-7.37 (m, 2H), 7.01 (dd, J=8.4, 2.50 Hz, 1H),6.63 (d, J=8.3 Hz, 1H), 3.77 (s, 3H), 2.30-2.40 (m, 1H), 1.99-2.24 (m,4H), 1.44 (d, J=42.4 Hz, 2H), 1.20-1.51 (m, 9H).

219C. MethylN-[(14S)-14-amino-9-oxo-10-oxa-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,2TFA: To a stirred solution of 219B (0.026 g, 0.057 mmol) in DCM (5 mL)at 0° C. was added TFA (0.500 mL, 6.49 mmol). The reaction was allowedto warm to rt. After 2 h, the reaction was concentrated and the crudematerial was washed with diethyl ether (6 mL) and dried to give thedesired product (0.015 g, 73%). MS(ESI) m/z: 357.2 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 9.94 (s, 1H), 9.35 (s, 1H), 8.61 (d, J=5.27 Hz, 1H),8.29 (br. s, 3H), 7.74 (s, 1H), 7.57-7.59 (m, 1H), 7.48-7.51 (m, 1H),7.39-7.40 (m, 1H), 7.35 (d, J=1.76 Hz, 1H), 4.71 (br. s, 1H), 3.91-3.94(m, 1H), 3.69 (s, 3H), 3.66 (s, 1H), 2.11-2.32 (m, 2H), 0.94-1.40 (m,2H).

Example 219. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-9-oxo-10-oxa-8,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt: 219C was coupled with Intermediate 25 according to theprocedure described in Example 2. An off-white solid (0.019 g, 48%) wasobtained. ¹H NMR (400 MHz, DMSO-d₆ with two drops of D₂O) δ 8.69 (d,J=5.77 Hz, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.76-7.83 (dd, J=6.80 Hz,J=1.60 Hz, 1H), 7.72 (d, J=5.27 Hz, 1H), 7.66 (d, J=8.53 Hz, 1H),7.48-7.55 (m, 2H), 7.38-7.46 (m, 2H), 5.13 (dd, J=9.20, 6.4 Hz, 1H),3.96-4.01 (m, 1H), 3.76-3.80 (m, 1H), 3.68 (s, 3H), 2.33 (s, 3H),2.23-2.26 (m, 2H), 1.42-1.53 (m, 1H), 1.05-1.12 (m 1H). MS(ESI) m/z:593.2 (M+H)⁺. Analytical HPLC RT=7.24 min (Method A).

Example 220 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-8-oxo-9,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

220A.(S)-(2-(1-((tert-Butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronicacid, TFA salt: To a solution of5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.198 g, 5.30 mmol)and (S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (1.0g, 3.54 mmol) in DMSO (10 mL) was added potassium acetate (1.041 g,10.61 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (0.289 g, 0.354 mmol). Thereaction was purged with argon for 10 min. The reaction mixture was thensealed and stirred for 12 h at 85° C. The reaction mixture was cooled tort and then it was diluted with EtOAc and washed with water. The aqueouslayer was extracted with EtOAc. The organic layers was washed withbrine, dried over sodium sulfate, filtered, and concentrated.Purification by reverse phase HPLC afforded the desired product (1.1 g,77%) as a white solid. MS(ESI) m/z: 293.2 (M+H)⁺. ¹H NMR (500 MHz, MeOD)δ 8.54 (d, J=5.8 Hz, 1H), 8.11 (s, 1H), 8.02 (dd, J=5.8, 0.6 Hz, 1H),5.79 (ddt, J=17.1, 10.2, 7.1 Hz, 1H), 5.11-5.03 (m, 2H), 4.86 (t, J=7.0Hz, 1H), 2.69-2.55 (m, 2H), 1.40 (br. s., 9H) ppm.

220B. (S)-Methyl2-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-nitrobenzoate:A solution of 220A (0.2 g, 0.492 mmol), methyl 2-bromo-5-nitrobenzoate(0.141 g, 0.542 mmol), Cs₂CO₃ (0.802 g, 2.462 mmol) in DME (8 mL) andwater (1.600 mL) was purged under argon for 5 min, thentetrakis(triphenylphosphine)palladium (0) (0.057 g, 0.049 mmol) wasadded, and the reaction mixture was heated at 90° C. After 4 h, thereaction was cooled to rt. The reaction mixture was partitioned betweenwater/brine and EtOAc and the layers were separated. The organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel chromatography afforded the desired product(0.176 g, 84%) as a white solid. MS(ESI) m/z: 428.2 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.78 (d, J=2.5 Hz, 1H), 8.65-8.61 (m, 1H), 8.41 (dd,J=8.4, 2.3 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.17-7.10 (m, 2H), 5.75-5.58(m, 2H), 5.11-5.02 (m, 2H), 4.90-4.83 (m, 1H), 3.74 (s, 3H), 2.68-2.59(m, 2H), 1.44 (s, 9H) ppm.

220C. (S)-Methyl2-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((methoxycarbonyl)amino)benzoate:To the solution of 220B (0.33 g, 0.772 mmol) in MeOH (7.72 mL) was addedammonium chloride (0.413 g, 7.72 mmol) and zinc (0.505 g, 7.72 mmol).The reaction was stirred at 55° C. for 5 h. The reaction was cooled tort, filtered, and the filtrate was concentrated. The residue waspartitioned between EtOAc and saturated NaHCO₃ and the layers wereseparated. The organic layer washed with water, brine, dried overNa₂SO₄, filtered, and concentrated to afford the aniline (0.317 g, 103%)as a yellow solid. MS(ESI) m/z: 398.2 (M+H)⁺. To a cooled (˜78° C.)clear solution of the aniline (0.317 g, 0.798 mmol) and pyridine (0.097mL, 1.196 mmol) in DCM (7.98 mL) was added dropwise methylchlorocarbonate (0.074 mL, 0.957 mmol). The reaction was stirred at −78°C. for 1 h, quenched with sat. NH₄Cl and then warmed to rt. The reactionwas diluted with DCM and water and the layers were separated. Theaqueous layer was extracted with DCM. The combined organic layers werewashed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated to give a brown foam. Purification by silica gelchromatography afforded the desired product (0.304 g, 84%) as a whitesolid. MS(ESI) m/z: 456.2 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.54 (d,J=5.0 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.28-7.21(m, 2H), 7.11 (s, 1H), 7.08 (dd, J=5.2, 1.7 Hz, 1H), 5.74-5.64 (m, 2H),5.09-5.01 (m, 2H), 4.88-4.81 (m, 1H), 3.81 (s, 3H), 3.66 (s, 3H),2.67-2.55 (m, 2H), 1.44 (s, 9H) ppm.

220D.(S)-2-(2-(1-((tert-Butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((methoxycarbonyl)amino)benzoicacid: To the solution of 220C (0.304 g, 0.667 mmol) in MeOH (6.67 mL)was added 1 N NaOH (2.67 mL, 2.67 mmol). The reaction was stirred at rt.After 48 h, the reaction was neutralized with 1 N HCl and then it wasconcentrated to remove the MeOH. The residue was extracted with EtOAc(2×). The organic layers were combined and washed with brine, dried overNa₂SO₄, filtered, and concentrated to afford 220D (0.291 g, 99%) as ayellow solid. MS(ESI) m/z: 442.2 (M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 8.45(d, J=5.2 Hz, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.73 (dd, J=8.3, 2.2 Hz, 1H),7.36 (d, J=1.1 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.26 (dd, J=5.2, 1.7 Hz,1H), 5.84-5.74 (m, 1H), 5.14-5.04 (m, 2H), 4.80-4.74 (m, 1H), 3.77 (s,3H), 2.65-2.45 (m, 2H), 1.42 (s, 9H) ppm.

220E. MethylN-{3-[(but-3-en-2-yl)carbamoyl]-4-{2-[(1S)-1-{[(ten-butoxy)carbonyl]amino}but-3-en-1-yl]pyridin-4-yl}phenyl}carbamate:To a solution of 220D (0.29 g, 0.657 mmol), but-3-en-2-amine, HCl (0.085g, 0.788 mmol), EDC (0.252 g, 1.314 mmol) and HOBT (0.201 g, 1.314 mmol)in DMF (5 mL) was added TEA (0.275 mL, 1.971 mmol). The reaction wasstirred at rt. After 24 h, the reaction was diluted with EtOAc, washedwith water (2×), brine, dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel chromatography afforded the desired product(0.31 g, 95%) as a white solid. MS(ESI) m/z: 495.3 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.54 (d, J=5.2 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.59 (d,J=1.9 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.26-7.20 (m, 3H), 5.74-5.54 (m,3H), 5.35-5.30 (m, 1H), 5.09-4.89 (m, 4H), 4.87-4.81 (m, 1H), 4.60-4.51(m, 1H), 3.80 (s, 3H), 2.66-2.54 (m, 2H), 1.43 (s, 9H), 1.05-1.01 (m,3H) ppm.

220F and 220G. MethylN-[(11E,14S)-14-{[(tert-butoxy)carbonyl]amino}-10-methyl-8-oxo-9,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl]carbamate,Diastereomer A and methylN-[(11E,14S)-14-{[(tert-butoxy)carbonyl]amino}-10-methyl-8-oxo-9,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl]carbamate,Diastereomer B: The procedure was followed as described for Example2J/2K, by replacing 21 with 220E. Purification by silica gelchromatography provided 220F (Diastereomer A) (0.073 g, 25%) as a brownsolid and 220G (Diastereomer B) (0.052 g, 18%) as a brown solid.Diastereomer A: MS(ESI) m/z: 467.2 (M+H)⁺. Diastereomer B: MS(ESI) m/z:467.2 (M+H)⁺.

Example 220. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-8-oxo-9,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: 220F (Diastereomer A) was converted to the title compound inthree steps (hydrogenation, Boc-deprotection, and amide formation usingIntermediate 25) according to the procedures described in Example 2. Awhite solid (0.008 g, 38%) was obtained as a homochiral compound.MS(ESI) m/z: 605.3 (M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 8.73 (d, J=6.1 Hz,1H), 8.30 (s, 1H), 8.04 (dd, J=6.1, 1.9 Hz, 1H), 7.95 (d, J=1.7 Hz, 1H),7.85-7.78 (m, 2H), 7.75-7.69 (m, 2H), 7.46 (ddd, J=8.0, 6.5, 1.7 Hz,1H), 7.41-7.35 (m, 1H), 5.23 (dd, J=11.8, 5.5 Hz, 1H), 4.28-4.21 (m,1H), 3.78 (s, 3H), 2.35 (d, J=0.8 Hz, 3H), 2.27-2.10 (m, 2H), 1.99-1.90(m, 1H), 1.63-1.53 (m, 1H), 1.37-1.26 (m, 1H), 1.04 (d, J=7.2 Hz, 3H),0.56-0.44 (m, 1H) ppm. Analytical HPLC RT=6.04 min.

Example 221 MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-8-oxo-9,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt

Example 221. MethylN-[(14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-10-methyl-8-oxo-9,16-diazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate,TFA salt: 220G (Diastereomer B) was converted to the title compound inthree steps (hydrogenation, Boc-deprotection, and amide formation usingIntermediate 25) according to the procedures described in Example 2. Awhite solid (0.005 g, 50%) was obtained as a homochiral compound.MS(ESI) m/z: 5.95 (M+H)⁺. ¹H NMR (500 MHz, MeOD) δ 8.71 (d, J=6.1 Hz,1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.93 (dd, J=6.1, 1.4 Hz, 1H), 7.75-7.68(m, 4H), 7.46 (ddd, J=8.0, 6.5, 1.7 Hz, 1H), 7.41-7.36 (m, 1H), 5.23(dd, J=9.9, 5.2 Hz, 1H), 4.14-4.06 (m, 1H), 3.77 (s, 3H), 2.36 (d, J=1.1Hz, 3H), 2.12-1.97 (m, 2H), 1.78-1.69 (m, 1H), 1.54-1.20 (m, 6H) ppm.Analytical HPLC RT=5.95 min.

Example 222 MethylN-[(11R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-11-methyl-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl]carbamate,TFA salt

222A. tert-ButylN-[(1S)-1-(4-{4-[(methoxycarbonyl)amino]-2-(3-methylpent-4-enamido)phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-en-1-yl]carbamate(mixture of diastereomers): 222A was prepared according to the proceduredescribed in Example 57E, by replacing pent-4-enoic acid with3-methylpent-4-enoic acid. MS(ESI) m/z: 628.4 (M+H)⁺. ¹H NMR (400 MHz,MeOD) δ 8.45 (d, J=2.01 Hz, 1H), 7.51-7.58 (m, 2H), 7.35 (d, J=7.03 Hz,1H), 5.80-5.94 (m, 2H), 5.61 (d, J=10.79 Hz, 1H), 5.36 (d, J=11.04 Hz,1H), 5.20 (s, 1H), 5.04-5.13 (m, 2H), 4.92-5.03 (m, 2H), 3.75 (s, 3H),3.62 (t, J=8.03 Hz, 2H), 2.73-2.87 (m, 3H), 2.40-2.57 (m, 2H), 1.45 (s,9H), 1.14 (t, J=6.78 Hz, 3H), 0.96 (td, J=8.03, 5.52 Hz, 2H), −0.01-0.04(m, 9H).

222B. tert-ButylN-[(12E,15S)-5-[(methoxycarbonyl)amino]-11-methyl-9-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl]carbamateand Z-isomer: A flame-dried RBF, equipped with condenser, containing asolution of 222A (1.1 g, 1.752 mmol) and p-toluenesulfonic acidmonohydrate (0.367 g, 1.927 mmol) in DCM (1600 mL) was degassed for 1 hwith nitrogen. The reaction mixture was refluxed for 1 h under nitrogenatmosphere. Next, a solution oftricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride(0.596 g, 0.701 mmol) in DCM (15 mL), purged with nitrogen for 10 min,was added slowly. The reaction was stirred overnight at 45° C. Thereaction was cooled to rt. The reaction mixture was washed withsaturated NaHCO₃ (2×250 mL), brine solution (250 mL), dried by Na₂SO₄,filtered and concentrated to give a gummy brown solid. Purificationusing silica gel chromatography gave the desired product (0.88 g, 84%)as a brown solid and a mixture of E and Z isomers. MS(ESI) m/z: 600.4(M+H)⁺.

222C (Diastereomer A). tert-ButylN-[(11R,15S)-5-[(methoxycarbonyl)amino]-11-methyl-9-oxo-17-{2-(trimethylsilyl)ethoxy]methyl}-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl]carbamateand 222D (Diastereomer B), tert-butylN-[(11S,15S)-5-[(methoxycarbonyl)amino]-11-methyl-9-oxo-17-{2-(trimethylsilyl)ethoxy]methyl}-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl]carbamateTo the solution of 222B (2.1 g, 3.50 mmol) in MeOH (100 mL) was addedplatinum(IV) oxide (0.159 g, 0.700 mmol) and the reaction was stirred atrt under hydrogen atmosphere. After 30 h, the reaction was stopped andfiltered through CELITE® washing with methanol (4×50 mL) and ethylacetate (4×50 mL). The filtrate was concentrated to give a brown solid.The diastereomers were separated by chiral HPLC using Chiral OD-H columnto give (Diastereomer A, 0.750 g, 34%) and (Diastereomer B, 0.700 g,33%). 222C (Diastereomer A): MS(ESI) m/z: 602.2 (M+H)⁺. [α]^(20.0)_(D)=−44.48 (c 0.5, MeOH). ¹H NMR (300 MHz, MeOD) δ 8.11 (d, J=2.17 Hz,1H), 7.39-7.45 (m, 2H), 7.33-7.38 (m, 1H), 5.50-5.59 (m, 2H), 5.33 (d,J=10.76 Hz, 1H), 3.75 (s, 3H), 3.60 (t, J=8.12 Hz, 2H), 2.36-2.49 (m,1H), 2.26-2.35 (m, 2H), 2.16-2.25 (m, 1H), 1.82-1.93 (m, 1H), 1.75-1.82(m, 1H), 1.46 (s, 9H), 1.22-1.33 (m, 1H), 1.07-1.16 (m, 1H), 1.04 (d,J=6.42 Hz, 3H), 0.95 (td, J=8.14, 4.49 Hz, 2H), 0.02 (s, 9H). 222D(Diastereomer B): MS(ESI) m/z: 602.2 (M+H)⁺. [α]^(20.0) _(D)=−66.40 (c0.5, MeOH). ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.66 (s, 1H),8.30 (d, J=2.26 Hz, 1H), 7.65 (s, 1H), 7.43-7.52 (m, 2H), 7.25 (dd,J=8.41, 2.13 Hz, 1H), 5.27-5.39 (m, 2H), 3.67 (s, 3H), 3.50-3.56 (m,2H), 2.53-2.60 (m, 2H), 2.46 (s, 1H), 2.04-1.95 (m, 2H), 1.93 (dd,J=13.30, 6.02 Hz, 2H), 1.41 (s, 9H), 0.99 (d, J=6.78 Hz, 3H), 0.89 (td,J=8.16, 3.26 Hz, 2H), −0.02 (s, 9H).

222E. MethylN-[(11R,15S)-15-amino-11-methyl-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl]carbamate,2HCl: A sealed tube containing 222C (0.050 g, 0.083 mmol) in 4 M HCl indioxane (1.5 mL, 49.4 mmol) was heated at 50° C. for 3 h. The reactionmixture was concentrated to give an off-white solid. Trituration frompetroleum ether (3×5 mL) and diethyl ether (2×7 mL) gave the desiredproduct (0.030 g, 97%) as an off white solid. MS(ESI) m/z: 372.2 (M+H)⁺.¹H NMR (400 MHz, MeOD) δ 7.64 (d, J=7.03 Hz, 2H), 7.44-7.50 (m, 2H),4.71 (dd, J=11.29, 4.27 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 1H), 2.54 (dd,J=13.68, 2.89 Hz, 1H), 2.38-2.44 (m, 1H), 2.09-2.22 (m, 2H), 1.96-2.04(m, 1H), 1.79 (d, J=6.27 Hz, 1H), 1.41 (d, J=9.54 Hz, 1H), 1.02 (d,J=6.53 Hz, 3H), 0.74 (d, J=6.78 Hz, 1H).

Example 222. MethylN-[(11R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-11-methyl-9-oxo-8,17,19-triazatricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl]carbamate,TFA salt: 222E was coupled with Intermediate 25 according to theprocedure described in Example 2. An off white solid (0.009 g, 14%) wasobtained. ¹H NMR (400 MHz, DMSO-d₆ two drops D₂O) δ 8.29-8.32 (m, 1H),8.18-8.21 (m, 1H), 7.75-7.81 (m, 1H), 7.48-7.54 (m, 2H), 7.40-7.46 (m,2H), 7.13-7.18 (m, 1H), 5.09 (d, J=12.30 Hz, 1H), 3.64 (s, 3H), 2.37 (s,3H), 2.24-2.36 (m, 2H), 2.17-2.05 (m, 2H), 1.99-2.10 (m, 2H), 1.78-1.45(m, 2H), 1.34 (d, J=13.80 Hz, 1H), 0.99 (d, J=6.78 Hz, 3H). MS(ESI) m/z:608.3 (M+H)⁺. Analytical HPLC RT=6.20 min (Method A).

Example 223 MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,17,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(18),2,4,6,15-pentaen-5-yl]carbamate,TFA salt

223A. tert-Butyl N-(1-diazo-2-oxohex-5-en-3-yl)carbamate: To a cooled(−40° C.) solution of 2-((t-butoxycarbonyl)amino)pent-4-enoic acid (15g, 69.7 mmol) in THF (250 mL) was added N-methylmorpholine (9.19 mL, 84mmol) followed by the dropwise addition of isobutyl chloroformate (10.98mL, 84 mmol). The reaction was stirred at −40° C. for 20 min, whereuponit was filtered to remove the salts. The filtrate was added to asolution of diazomethane (4.39 g, 105 mmol) in Et₂O (500 mL) [Generatedfrom 1-methyl-3-nitro-1-nitrosoguanidine]. The reaction mixture wasstirred at −40° C. for 3 h and then the reaction was allowed to warm tort. After 1 h, the reaction was purged with nitrogen for 30 min toremove the excess diazomethane. The reaction mixture was washed with asaturated solution of NaHCO₃ (2×100 mL), water (2×50 mL), brine solution(1×80 mL), dried by Na₂SO₄, filtered and concentrated to give a yellowsolid (16 g). Purification by normal phase chromatography afforded thedesired product (12.5 g, 75%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃)δ 5.66-5.83 (m, 1H), 5.48 (br. s., 1H), 5.19 (dd, J=3.21, 1.79 Hz, 1H),5.03-5.16 (m, 2H), 4.24 (br. s., 1H), 2.35-2.62 (m, 2H), 1.46 (s, 9H).

223B. tert-Butyl N-(1-bromo-2-oxohex-5-en-3-yl)carbamate: To a cooled(−15° C.) suspension of 223A (15 g, 62.7 mmol) in diethyl ether (500 mL)was added dropwise HBr (˜47% in water) (18.11 mL, 157 mmol). After 15min., the reaction was allowed to warm slowly to 0° C. over 2.5 h. Thereaction was diluted with diethyl ether (100 mL) and the reaction waswashed with water (2×100 mL), saturated solution of NaHCO₃ (1×80 mL),brine solution (1×80 mL), dried by Na₂SO₄, filtered and concentrated togive the desired product (17 g, 93%) as a viscous yellow liquid whichsolidified in the refrigerator. ¹H NMR (400 MHz, CDCl₃) δ 5.62-5.76 (m,1H), 5.12-5.21 (m, 2H), 5.08 (br. s., 1H), 4.57 (d, J=6.00 Hz, 1H),3.99-4.12 (m, 2H), 2.38-2.67 (m, 2H), 1.43 (s, 9H).

223C. tert-Butyl N-[1-(1H-imidazol-4-yl)but-3-en-1-yl]carbamate: Apressure tube containing a solution of 223B (28 g, 96 mmol), formamidineacetate (19.95 g, 192 mmol) and K₂CO₃ (53.0 g, 383 mmol) in DMF (200 mL)was heated at 100° C. overnight. The reaction mixture was cooled to rtand concentrated. The residue was partitioned between water (200 mL) andethyl acetate (500 mL) and the layers were separated. The aqueous layerwas extracted with ethyl acetate (2×200 mL). The organic layers werecombined and washed with brine (1×100 mL), dried by Na₂SO₄, filtered andconcentrated to give the desired product (25.5 g, 84%) as a gummy brownsolid. This was used in the next step without purification. MS(ESI) m/z:238.2 (M+H)⁺.

223D. tert-ButylN-[1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)but-3-en-1-yl]carbamate:To a cooled (0° C.) solution of 223C (25.5 g, 107 mmol) in THF (260 mL)was added sodium hydride (4.73 g, 118 mmol). Following the addition, thereaction was allowed to warm to rt. After 30 min., the reaction wascooled to 0° C. and SEM-Cl (19.06 mL, 107 mmol) was added dropwise. Thereaction was allowed to warm to rt and stirred overnight. The reactionmixture was concentrated to give a brown gummy solid. Purification bynormal phase chromatography gave the desired product (11.5 g, 70%) as agummy, brown solid. MS(ESI) m/z: 368.4 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.51 (d, J=1.25 Hz, 1H), 6.87 (s, 1H), 5.71 (dd, J=17.13, 10.13 Hz, 1H),5.20 (s, 2H), 4.99-5.10 (m, 3H), 4.73 (dd, J=13.88, 6.38 Hz, 1H),3.43-3.48 (m, 2H), 2.55-2.63 (m, 2H), 1.43 (s, 9H), 0.86-0.91 (m, 2H),0.02-0.03 (m, 9H).

223E. tert-ButylN-[1-(2-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)but-3-en-1-yl]carbamate:To a cooled (−78° C.) solution of 223D (5.0 g, 13.60 mmol) in THF (100mL) was added dropwise nBuLi (1.6 M in hexanes) (25.5 mL, 40.8 mmol).After 2 h, N-bromosuccinimide (2.421 g, 13.60 mmol) was added. After 2h, the reaction mixture was quenched with a solution of saturated NH₄Cl(30 mL). The reaction mixture extracted with ethyl acetate (3×50 mL).The organic layers were combined and washed with brine (1×50 mL), driedby Na₂SO₄, filtered and concentrated to give a gummy yellow solid.Purification by normal phase chromatography gave the desired product(2.0 g, 26.5%) as a gummy, brown solid. MS(ESI) m/z: 446.0 (M+H)⁺. ¹HNMR (300 MHz, CDCl₃) δ 6.95 (s, 1H), 5.63-5.78 (m, 1H), 5.22 (s, 2H),5.02-5.14 (m, 3H), 4.64-4.74 (m, 1H), 3.50-3.57 (m, 2H), 2.58 (t, J=6.61Hz, 2H), 1.44 (s, 9H), 0.89-0.96 (m, 2H), 0.01 (s, 9H).

223F. tert-ButylN-[(1S)-1-[2-(2-amino-4-nitrophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl]but-3-en-1-yl]carbamate(Enantiomer I) and 223G. tert-ButylN-[(1R)-1-[2-(2-amino-4-nitrophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl]but-3-en-1-yl]carbamate(Enantiomer II): To a solution of 223E (3 g, 6.72 mmol) and(2-(2-amino-4-nitrophenyl)-5-methyl-1,3,2-dioxaborinan-5-yl)methylium(5.02 g, 20.16 mmol) in toluene (40 mL) was added phosphoric acid,potassium salt (4.28 g, 20.16 mmol) and water (10 mL). The reactionmixture was purged with nitrogen for 15 min. Next, PdCl₂(dppf)-CH₂Cl₂adduct (0.274 g, 0.336 mmol) was added and the reaction was heated at110° C. After 3 h, the reaction was cooled to rt. The reaction mixturewas diluted with ethyl acetate (80 mL) and then it was washed withsaturated NaHCO₃ (50 mL), water (50 mL), brine (50 mL), dried overNa₂SO₄, filtered and concentrated to give a gummy brown solid.Purification by normal phase chromatography gave a gummy brown solid.The enantiomers were separated by chiral HPLC using CHIRALPAK® AD-H250×21 mm column (mobile phase: CO₂:80%, solvent: 20% (0.5% DEA inMethanol)) to give 223F (Enantiomer I, 0.42 g, 13%) and 223G (EnantiomerII, 0.545 g, 16%). 223F (Enantiomer I): MS(ESI) m/z: 503.9 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆ with two drops D₂O) δ 7.56-7.62 (m, 2H), 7.39 (dd,J=8.53, 2.51 Hz, 1H), 7.20 (s, 1H), 5.65-5.75 (m, 1H), 5.23 (s, 2H),4.95-5.08 (m, 2H), 4.55 (d, J=8.53 Hz, 1H), 3.40 (t, J=8.03 Hz, 2H),2.32-2.49 (m, 2H), 1.33 (s, 9H), 0.69-0.77 (m, 2H), −0.14 (s, 9H). 223G(Enantiomer II): MS(ESI) m/z: 503.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆with two drops D₂O) δ 7.60-7.64 (m, 2H), 7.38 (dd, J=8.78, 2.26 Hz, 1H),7.22 (s, 1H), 5.66-5.77 (m, 1H), 5.24 (s, 2H), 4.95-5.09 (m, 2H), 4.57(d, J=8.53 Hz, 1H), 3.44 (t, J=8.03 Hz, 2H), 2.32-2.48 (m, 2H), 1.35 (s,9H), 0.73-0.80 (m, 2H), −0.11 (s, 9H).

223H. tert-ButylN-[(1S)-1-(2-{2-[(2R)-2-methylbut-3-enamido]-4-nitrophenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)but-3-en-1-yl]carbamate:To a cooled (0° C.) solution of 223F (0.650 g, 1.291 mmol) in DCM (10mL) was added pyridine (0.313 mL, 3.87 mmol) followed by DMAP (0.015 g,0.129 mmol). Next, freshly prepared Intermediate 48 (0.383 g, 3.23 mmol)in DCM (0.5 mL) was added dropwise. After 20 min, the reaction wasconcentrated. Purification by normal phase chromatography provided thedesired product (0.740 g, 98%) as a yellow oil. MS(ESI) m/z: 586.5(M−H). ¹H NMR (300 MHz, MeOD) δ 9.34 (t, J=1.37 Hz, 1H), 8.05 (d, J=1.32Hz, 2H), 7.35 (s, 1H), 6.98 (d, J=8.12 Hz, 1H), 5.76-6.04 (m, 2H), 5.36(m, 2H), 5.04-5.26 (m, 4H), 4.80 (d, J=6.66 Hz, 1H), 3.65 (t, J=7.8 Hz,2H), 3.25-3.30 (m, 1H), 2.64-2.79 (m, 1H), 2.50-2.61 (m, 1H), 1.46 (s,9H), 1.32 (d, J=6.9, 3H), 0.93 (t, J=8.1 Hz, 3H), 0.01 (s, 9H).

223I. tert-ButylN-[(10R,11E,14S)-10-methyl-5-nitro-9-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-8,17,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(18),2,4,6,11,15-hexaen-14-yl]carbamate:A flame-dried 3 neck 1 L RBF containing the solution of 223H (0.42 g,0.717 mmol) and p-toluenesulfonic acid monohydrate (0.15 g, 0.789 mmol)in DCM (700 mL) was purged with argon for 1 h. Next, the reaction waswarmed to reflux. After 1 h, a solution oftricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride(0.244 g, 0.287 mmol) in DCM (6 mL) was added dropwise. The reaction wasallowed to stir at reflux overnight. The reaction mixture was cooled tort, washed with saturated NaHCO₃ (2×80 mL), brine (80 mL), dried byNa₂SO₄, filtered and concentrated to give a gummy brown solid.Purification by normal phase chromatography afforded the title compound(0.225 gm, 56%) as a gummy, yellow solid. MS(ESI) m/z: 558.5 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 12.80 (br. s., 1H), 9.33 (br. s., 1H), 7.94-8.04(m, 2H), 6.99 (d, J=8.00 Hz, 1H), 6.01-5.25 (m, 1H), 5.19-5.27 (m, 4H),5.14 (d, J=7.50 Hz, 2H), 3.64-3.73 (m, 2H), 3.60 (m, 2H), 1.54 (s, 9H),0.94-1.01 (m, 3H), 0.00 (s, 9H).

223J. tert-ButylN-[(10R,14S)-5-amino-10-methyl-9-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-8,17,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(18),2(7),3,5,15-pentaen-14-yl]carbamate:A solution of 2231 (0.210 g, 0.377 mmol) in EtOAc (20 mL) was purgedwith nitrogen and vacuum. This was repeated 3 times. Next, platinum(IV)oxide (0.043 g, 0.188 mmol) was added and the reaction was purged withH₂ gas for several minutes (H₂ filled in balloon). The reaction wasstirred vigorously under a hydrogen atmosphere. After 16 h, the reactionwas diluted with methanol (5 mL) and then it was filtered throughCELITE® bed, washing with methanol (2×5 mL). The filtrate wasconcentrated to give 223J (0.200 g, 95%) as a white solid. MS(ESI) m/z:530.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.15 (br. s., 1H), 7.56 (d,J=8.51 Hz, 1H), 7.48 (d, J=2.25 Hz, 1H), 6.86 (s, 1H), 6.46 (dd, J=8.50,2.50 Hz, 1H), 5.09-5.18 (m, 3H), 5.29-5.12 (m, 1H), 3.90-3.60 (m, 2H),3.55-3.62 (m, 2H), 2.45-1.90 (m, 1H), 1.86-1.97 (m, 2H), 1.66-1.78 (m,3H), 1.47 (s, 9H), 1.26 (s, 2H), 0.92-0.98 (m, 3H), 0.01 (s, 9H).

223K. tert-ButylN-[(10R,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-17-{[2-(trimethylsilyl)ethoxy]methyl}-8,17,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(18),2(7),3,5,15-pentaen-14-yl]carbamate:To the cooled (0° C.) solution of 223J (0.195 g, 0.368 mmol) in DCM (5mL) was added pyridine (0.045 mL, 0.552 mmol) followed by the dropwiseaddition of methyl chloroformate (0.043 mL, 0.552 mmol). After 10 min.,the reaction was allowed to warm to rt. After 1 h, the reaction wasdiluted with DCM (30 mL) and then it was washed with saturated NaHCO₃(2×20 mL), brine (20 mL), dried by Na₂SO₄, filtered and concentrated togive a gummy brown solid. Purification by normal phase chromatographyprovided the title compound (0.145 g, 67%) as a yellow solid. MS(ESI)m/z: 588.2 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ 7.71 (d, J=8.53 Hz, 1H),7.64 (s, 1H), 7.44 (dd, J=8.28, 2.26 Hz, 1H), 7.12 (s, 1H), 5.19-5.27(m, 2H), 3.78 (s, 3H), 3.64-3.73 (m, 2H), 2.58 (t, J=6.27 Hz, 1H),2.01-2.11 (m, 1H), 1.76 (dt, J=6.40, 3.58 Hz, 2H), 1.52-1.62 (m, 2H),1.47 (s, 9H), 1.35-1.41 (m, 2H), 1.07 (d, J=7.03 Hz, 3H), 0.99 (dt,J=8.91, 6.59 Hz, 2H), 0.05 (s, 9H).

223L. MethylN-[(10R,14S)-14-amino-10-methyl-9-oxo-8,17,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(18),2(7),3,5,15-pentaen-5-yl]carbamate:To a solution of 223K (0.030 g, 0.051 mmol) in DCM (1 mL) was added TFA(1 mL, 12.98 mmol). After 1 h, additional TFA (0.4 mL) was added. After1 h, the reaction was concentrated to give a white solid. Petroleumether (5 mL) was added and the mixture was stirred. The solvent wasremoved with a dropper. This was repeated with diethyl ether (2×7 mL)and the solid was dried under high vacuum to give the desired product(0.040 g, 93%) as a white solid. MS(ESI) m/z: 358.4 (M+H)⁺. ¹H NMR (400MHz, MeOD) δ 7.68 (d, J=2.01 Hz, 1H), 7.62 (d, J=8.53 Hz, 1H), 7.50-7.55(m, 1H), 7.39 (s, 1H), 4.63 (dd, J=8.78, 5.77 Hz, 1H), 3.79 (s, 3H),2.17-2.30 (m, 1H), 1.81-1.95 (m, 2H), 1.65-1.80 (m, 2H), 1.34-1.55 (m,2H), 1.12 (d, J=7.03 Hz, 3H).

Example 223. MethylN-[(10R,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,17,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(18),2,4,6,15-pentaen-5-yl]carbamate,TFA salt: To a solution of 223L (0.010 g, 0.028 mmol) in DMF (1.0 mL)was added Intermediate 21 (0.0071 g, 0.028 mmol), EDC (0.0085 mg, 0.042mmol), HOBT (0.0064 mg, 0.042 mmol) and Hunig's base (0.024 mL, 0.140mmol). The reaction was stirred at rt overnight. The reaction wasconcentrated to give a gummy solid. Purification by reverse phase HPLCafforded the title compound (2.8 mg, 13%) as an off-white solid. ¹H NMR(400 MHz, MeOD) δ 7.79-7.79 (m, 2H), 7.58-7.66 (m, 2H), 7.46-7.53 (m,2H), 7.13 (s, 1H), 5.37 (t, J=4.52 Hz, 1H), 3.78 (s, 3H), 2.68 (m, 1H),2.54 (d, J=1.00 Hz, 3H), 2.18-2.25 (m, 2H), 2.00-2.09 (m, 2H), 1.63 (m,2H), 1.23 (d, J=7.03 Hz, 3H). MS(ESI) m/z: 593.0 (M+H)⁺. Analytical HPLCRT=6.38 min.

Example 224 MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,17,18-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt

224A. tert-Butyl N-[(3,6-dichloropyridazin-4-yl)methyl]carbamate: Amixture of 3,6-dichloropyridazine (0.765 g, 5.14 mmol) in water (25 mL)was heated to 75° C. 2-((tert-Butoxycarbonyl)amino)acetic acid (1 g,5.71 mmol) and ammonium formate (0.072 g, 1.142 mmol) were added. Then,a solution of silver nitrate (0.194 g, 1.142 mmol) in water (1 mL) wasadded dropwise over 2 min. To the resulting dark brown solution wasadded dropwise a solution of ammonium persulfate (5.21 g, 22.83 mmol) inwater (30 mL) over 25 min. A purple precipitate formed. The reactionmixture was stirred for additional 40 min, and then cooled to rt. Thereaction mixture was poured onto ice, basified with aq. ammonia, keepingthe temperature below 5° C. The reaction mixture was extracted withethyl acetate and the organic layer was dried over sodium sulfate,filtered and concentrated. Purification by normal phase chromatographyafforded the desired product (0.3 g, 18%) as an off-white solid. MS(ESI)m/z: 278.1 (M+H)⁺. ¹H NMR (300 MHz, CDCl₃) δ 7.51 (s, 1H), 5.15 (br. s.,1H), 4.40 (s, 2H), 1.49 (s, 9H).

224B. tert-ButylN-[1-(3,6-dichloropyridazin-4-yl)but-3-en-1-yl]carbamate: To a cooled(−78° C.) solution of 224A (2 g, 7.19 mmol) in tetrahydrofuran (25 mL)was added TMEDA (3.2 mL, 21.20 mmol). To the resulting light green colorsolution was added dropwise n-butyllithium (1.6 M in hexane) (25.2 mL,40.3 mmol). Following the addition, the reaction was allowed to warm to−40° C. over 30 min. The reaction was cooled to −78° C. and then allylbromide (2.7 mL, 31.2 mmol) was added dropwise. After 1 h, the reactionwas quenched with the addition of saturated ammonium chloride (25 mL)and the reaction was warmed to rt. The reaction mixture was diluted withethyl acetate, washed with 1 N HCl (15 mL), saturated sodium bicarbonate(15 mL), brine (15 mL), dried over Na₂SO₄, filtered, and concentrated.Purification by normal phase chromatography gave the desired product(0.93 g, 41%) as a buff colored solid. MS(ESI) m/z: 318.2 (M+H)⁺. ¹H NMR(400 MHz, MeOD) δ 7.76-7.76 (m, 1H), 5.85-5.86 (m, 1H), 5.17 (d, J=1.00Hz, 2H), 4.88-4.88 (m, 1H), 2.55-2.57 (m, 1H), 2.41-2.43 (m, 1H),1.42-1.44 (m, 9H).

224C. tert-ButylN-[(1S)-1-[6-(2-amino-4-nitrophenyl)-3-chloropyridazin-4-yl]but-3-en-1-yl]carbamate(Enantiomer I) and 224D. tert-ButylN-[(1R)-1-[6-(2-amino-4-nitrophenyl)-3-chloropyridazin-4-yl]but-3-en-1-yl]carbamate(Enantiomer II): A mixture of 224B (0.5 g, 1.571 mmol) in toluene (10mL) and ethanol (1 mL) was degassed using nitrogen gas. Next,2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitroaniline (0.452 g, 1.807mmol) and sodium carbonate (0.500 g, 4.71 mmol) were added. The reactionmixture was degassed with nitrogen for 10 min. Then,tetrakis(triphenylphosphine)palladium(0) (0.082 g, 0.071 mmol) was addedand the reaction was heated to 100° C. After 16 h, the reaction wascooled to rt and filtered through a plug of CELITE®. The filtrate waswashed with water, brine, dried over Na₂SO₄, filtered, and concentrated.Purification by normal phase chromatography gave the desired product(0.2 g, 30%) as a pale yellow solid. The enantiomers were separated bychiral HPLC using CHIRALCEL® OJ-H to give 224C (Enantiomer I) as a paleyellow solid and 224D (Enantiomer II) as a pale yellow solid. 224C(Enantiomer I): (ESI) m/z: 420.2 (M+H)⁺. ¹H NMR (300 MHz, MeOD) δ 8.11(s, 1H), 7.72-7.79 (m, 2H), 7.54 (dd, J=8.73, 2.31 Hz, 1H), 5.83-5.95(m, 1H), 5.14-5.20 (m, 2H), 5.01 (br. s, 1H), 2.41-2.71 (m, 2H),1.39-1.49 (m, 9H). [α]²⁰ _(D)=−62 (c 0.1, MeOH). 224D (Enantiomer II):MS(ESI) m/z: 420.2 (M+H)⁺. ¹H NMR (300 MHz, MeOD) δ 8.11 (s, 1H),7.74-7.76 (m, 2H), 7.54 (dd, J=8.69, 2.36 Hz, 1H), 5.81-5.95 (m, 1H),5.14-5.20 (m, 2H), 4.96-5.06 (m, 1H), 2.14-2.43 (m, 2H), 1.39-1.50 (m,9H). [α]²⁰ _(D)=78.4 (c 0.1, MeOH).

224E. tert-ButylN-[(1S)-1-{3-chloro-6-[2-(2-methylbut-3-enamido)-4-nitrophenyl]pyridazin-4-yl}but-3-en-1-yl]carbamate:To a cooled (0° C.) solution of 224C (0.1 g, 0.238 mmol) indichloromethane (1 mL) and pyridine (0.058 mL, 0.715 mmol) was addedIntermediate 48 (0.031 g, 0.262 mmol). The reaction was allowed to warmto rt. After 35 min., the reaction was concentrated. Purification bynormal phase chromatography afforded the desired product (0.1 g, 84%) asa pale yellow semi solid. MS(ESI) m/z: 502.2 (M+H)⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 10.63-10.64 (d, J=6.03 Hz, 1H), 8.93-8.95 (m, 1H), 8.17-8.19(m, 2H), 7.92-7.93 (m, 1H), 7.70-7.71 (m, 1H), 5.87-5.91 (m, 2H),5.13-5.20 (m, 4H), 4.99-5.11 (m, 1H), 3.19-3.22 (m, 1H), 2.51-2.53 (m,1H), 2.45-2.49 (m, 1H), 1.72-1.79 (m, 1H), 1.36-1.51 (m, 9H), 1.27 (d,J=6.73 Hz, 3H).

224F. tert-ButylN-[(1S)-1-{6-[4-amino-2-(2-methylbut-3-enamido)phenyl]-3-chloropyridazin-4-yl}but-3-en-1-yl]carbamate:A mixture of 224E (0.24 g, 0.478 mmol) in acetic acid (5 mL) and water(1.667 mL) was heated to 70° C. under N₂. Next, finely powdered iron(0.134 g, 2.391 mmol) was added. After 30 min, the reaction was cooledto rt and filtered through CELITE®. The filtrate was neutralized with10% NaOH solution. The mixture was extracted with DCM. The organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentrated.The crude product was washed with diethyl ether (2×5 mL) and dried togive the desired product (0.19 g, 84%) as a pale pink solid. Thismaterial was used in the next step without further purification. MS(ESI)m/z: 502.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.61-11.63 (d, J=7.21Hz, 1H), 8.07-8.32 (m, 1H), 7.65-7.69 (m, 2H), 7.46-7.48 (m, 1H),6.46-6.48 (m, 1H), 5.80-5.88 (m, 4H), 5.20-5.24 (m, 1H), 5.12-5.14 (m,3H), 4.99-5.10 (m, 1H), 3.19-3.22 (m, 1H), 2.51-2.53 (m, 1H), 2.45-2.49(m, 1H), 1.72-1.79 (m, 1H), 1.36 (s, 9H), 1.27 (m, 3H).

224G. tert-ButylN-[(1S)-1-(3-chloro-6-{4-[(methoxycarbonyl)amino]-2-(2-methylbut-3-enamido)phenyl}pyridazin-4-yl)but-3-en-1-yl]carbamate:To a cooled (−60° C.) solution of 224F (0.06 g, 0.127 mmol) in DCM (4mL) was added pyridine (0.011 mL, 0.140 mmol). Next, a solution ofmethyl chloroformate (9.85 μL, 0.127 mmol) in DCM was added dropwise.After 30 min, the reaction was diluted with DCM and washed withsaturated sodium bicarbonate, brine, dried over Na₂SO₄, filtered, andconcentrated. Purification by normal phase chromatography gave thedesired product (0.021 g, 31%) as a pale pink solid. MS(ESI) m/z: 530.2(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83-10.84 (d, J=7.21 Hz, 1H), 9.96(s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.70-7.71 (m, 1H), 7.61-7.63 (dd,J=8.28, 6.90 Hz, 1H), 7.48-7.51 (m, 1H), 5.77-5.92 (m, 2H), 5.12-5.20(m, 4H), 4.92-5.10 (m, 1H), 3.70 (s, 3H), 3.14-3.18 (m, 1H), 2.45-2.50(m, 2H), 1.72-1.79 (m, 1H), 1.36 (s, 9H), 1.27 (d, J=7.03 Hz, 3H).

224H. MethylN-[(11E,14S)-14-{[(tert-butoxy)carbonyl]amino}-16-chloro-10-methyl-9-oxo-8,17,18-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl]carbamate:A solution of 224G (0.1 g, 0.189 mmol) in 1,2-dichloroethane (40 mL) wasdegassed with argon for 25 mins Next, Grubbs II (0.064 g, 0.075 mmol)was added and the reaction was heated at 120° C. under microwaveconditions for 30 min. The reaction mixture was filtered throughCELITE®, and the filtrate was washed with saturated sodium bicarbonate,brine, dried over Na₂SO₄, filtered and concentrated. Purification bynormal phase chromatography gave 224H (0.02 g, 22%) as an off whitesolid. MS(ESI) m/z: 501.2 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.98 (s,1H), 7.9-8.01 (m, 2H), 7.79-7.85 (m, 1H), 7.74 (s, 1H), 7.34-7.4 (m,2H), 5.82-5.93 (m, 1H), 5.68-5.79 (m, 1H), 4.94-5.06 (m, 1H), 3.71 (s,3H), 3.20-3.29 (m, 1H), 2.38-0.63 (m, 2H), 1.30 (s, 9H), 0.90-0.97 (m,3H).

224I. MethylN-[(10S,14S)-14-{[(tert-butoxy)carbonyl]amino}-10-methyl-9-oxo-8,17,18-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate:A mixture of 224H (0.025 g, 0.050 mmol) and ammonium formate (0.001 mg,0.025 mmol) in methanol (10 mL) was purged with N₂ for 10 min. Next,Pd/C (0.042 g, 0.398 mmol) was added to the reaction. After 16 h, thereaction was filtered through CELITE® and the filtrate was concentrated.The crude material was washed with diethyl ether (2×5 mL) and dried togive the desired product (0.019 g, 81%) as a black solid. MS(ESI) m/z:470.2 (M+H)⁺.

224J. MethylN-[(10S,14S)-14-amino-10-methyl-9-oxo-8,17,18-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate:To a cooled (0° C.) solution of 2241 (0.027 g, 0.058 mmol) in DCM (3 mL)was added TFA (0.250 mL, 3.24 mmol). The reaction was allowed to warm tort. After 2 h, the reaction was concentrated. The crude material waswashed with diethyl ether (2×3 mL), ethyl acetate (2×5 mL), DCM (5×15mL) and dried to give the desired product (0.018 g, 52%) as a reddishbrown solid. MS(ESI) m/z: 370.6 (M+H)⁺.

Example 224. MethylN-[(10S,14S)-14-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,17,18-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-5-yl]carbamate,TFA salt: To a solution of 224J (0.018 g, 0.049 mmol) in DMF (1 mL) wasadded Intermediate 21 (0.012 g, 0.049 mmol), HOBT (0.011 g, 0.073 mmol),EDC (0.014 g, 0.073 mmol), and DIPEA (0.043 mL, 0.244 mmol). Thereaction mixture was stirred at rt overnight. The reaction wasconcentrated to give a gummy solid. Purification by reverse phase HPLCprovided the desired product (3.5 mg, 12%) as an off white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.96 (s, 1H), 9.59 (s, 1H), 9.35 (d, J=7.53 Hz,1H), 9.23 (d, J=1.76 Hz, 1H), 8.32 (s, 1H), 7.95 (ddd, J=8.28, 6.90,1.63 Hz, 1H), 7.69-7.78 (m, 1H), 7.86 (d, J=8.53 Hz, 1H), 7.49-7.60 (m,2H), 7.44 (d, J=2.0 Hz, 1H), 4.99-5.11 (m, 1H), 3.71 (s, 3H), 2.40 (s,3H), 2.26 (dd, J=15.56, 7.53 Hz, 1H), 1.89-2.04 (m, 2H), 1.63-1.75 (m,1H), 1.46-1.57 (m, 1H), 1.30-1.43 (m, 2H), 1.13 (d, J=7.03 Hz, 3H).MS(ESI) m/z: 607.2 (M+H)⁺. Analytical HPLC RT=8.40 min (Method A).

The following Examples in Table 12 were made by using coupling acidswith amines. The acids used are as indicated in the below table in theIntermediate section. Various coupling reagents could be used other thanthe one described in Example 34 like BOP, PyBop, EDC/HOBt, HATU or T3P.Boc and SEM deprotection was achieved when necessary.

TABLE 12 Example RT, min # Stereochemistry Structure M + H Method 225Homochiral

581.2 4.63 D 226 Homochiral

635.6 8.42 A 227 Homochiral

635.6 8.22 A 228 Homochiral

621.6 7.10 A 229 Homochiral

608.3 6.00 A 230 Homochiral

606.3 6.13 A 231 Diastereomer mixture

600.1 5.99 A 232 Homochiral

623.0 8.15 A 233 Homochiral

623.0 8.02 A 234 Homochiral

591.0 5.91 A 235 Homochiral

622.9 8.66 A 236 Homochiral

622.9 8.79 A 237 Homochiral

638.3 5.95 A 238 Homochiral

638.3 6.00 A 239 Homochiral

628.2 7.54 A 240 Homochiral

624.3 6.70 A 241 Homochiral

634.9 6.85 A 242 Homochiral

635.0 6.25 B 243 Homochiral

621.1 4.99 A 244 Homochiral

591.9 5.24 A 245 Homochiral

579.9 5.24 A 246 Homochiral

606.3 8.15 A 247 Homochiral

640.2 9.86 A 248 Homochiral

640.3 9.70 A 249 Homochiral

598.0 5.30 A 250 Homochiral

598.1 6.28 A 251 Homochiral

649.3 5.20 D 252 Homochiral

638.1 5.06 E 253 Diastereomer mixture

623.2 7.50 A 254 Homochiral

623.1 7.50 A 255 Homochiral

623.1 7.50 A 256 Homochiral

621.0 4.91 A 257 Homochiral

635.1 5.19 A 258 Homochiral

635.9 7.25 A 259 Homochiral

622.0 6.20 B 260 Homochiral

622.0 6.22 B 261 Homochiral

650.2 3.59 B 262 Homochiral

594.2 5.75 A 263 Homochiral

593.8 6.31 A 264 Homochiral

592.0 6.24 A 265 Homochiral

609.4 6.96 A 266 Homochiral

605.0 8.47 A 267 Homochiral

605.0 8.40 A 268 Homochiral

579.2 6.33 A 269 Homochiral

594.1 7.00 A 270 Homochiral

579.2 7.04 A 271 Homochiral

595.5 6.48 A 272 Homochiral

609.4 6.75 A 273 Homochiral

594.2 6.19 A 274 Homochiral

609.3 6.43 A 275 Homochiral

609.3 6.60 A 276 Homochiral

594.0 6.14 A 277 Homochiral

594.1 5.02 D 278 Diastereomer mixture

594.2 5.94 6.05 D 279 Homochiral

606.2 9.27 A 280 Homochiral

606.1 7.19 A 281 Homochiral

What is claimed is:
 1. A compound of Formula (Ia):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein: ring A is selected from aryl and a 5- to6-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NH, N(C₁₋₄ alkyl), S(O)_(p), and O, wherein said aryland heterocycle are optionally substituted with R¹; ring B is a 5- to6-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NH, S(O)_(p), and O, wherein said heterocycle isoptionally substituted with R¹⁰; ring C is a 4- to 6-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NR⁹, S(O)_(p), and O, wherein said heterocycle is optionallysubstituted with R²; X is selected from C₄₋₈ alkylene and C₄₋₈alkenylene, wherein said alkylene and alkenylene are substituted with R⁴and R⁵; alternatively one or more of the carbon atoms of said alkyleneand alkenylene may be replaced by O, C═O, S(O)_(p), NH, and N(C₁₋₄alkyl); Y is selected from —CR⁶R⁷—NH— and —NH—CR⁶R⁷—; R¹ is selectedfrom H, halogen, NO₂, C₁₋₆ alkyl, OH, haloalkyl, alkoxy, haloalkoxy,—C(═O)C₁₋₃ alkyl, and CN; R² is selected from H, ═O, OH, NH₂, CF₃,halogen, C₁₋₄ alkyl (optionally substituted with OH), C₁₋₃ alkoxy, andC(O)C₁₋₃ alkyl; R³ is selected from H and C₁₋₄ alkyl; alternatively, R²and R³, together with the atoms to which they are directly or indirectlyattached, form a ring; R⁴ and R⁵ are independently selected from H,halogen, C₁₋₆ alkyl, OH, NH₂, —CH₂NH₂, C₁₋₄ haloalkyl, —OCH₂F, —OCHF₂,—OCF₃, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, —CH₂OH, and—CH₂O(C₁₋₄ alkyl); when R⁴ and R⁵ are not attached to the same carbonatom, they may be taken together with the carbon atoms to which they areattached to form a carbocycle; R⁶ is selected from H, halogen, C(O)OH,and C(O)O(C₁₋₄ alkyl); R⁷ is selected from H, C₁₋₄ alkyl, and CF₃;alternatively, R⁶ and R⁷ together are ═O; R⁸ is, independently at eachoccurrence, selected from H, halogen, haloalkyl, CN, —(CH₂)_(n)OH,NR¹²R¹², —CH₂NH₂, C(O)OH, —(CH₂)_(n)—NHC(O)OR¹², —NHC(O)R¹²,—NHC(O)C(O)R¹², —NHC(N—CN)NHR¹², —NHC(NH)NHR¹², —N═CHNR¹²R¹²,—NHC(O)NR¹²R¹², —NHS(O)₂C₁₋₄ alkyl, —(CH₂)_(n)—CONR¹²R¹²,—(CH₂)_(n)C(O)O(C₁₋₄ alkyl), —NHC(O)OCH₂(C(CH₂)₂)O—(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)—C₃₋₁₀ carbocycle, and —(CH₂)_(n)-4-10-memberedheterocycle wherein said carbocycle and heterocycle are optionallysubstituted with R¹³; R⁹ is selected from H and C₁₋₄ alkyl; R¹⁰ isselected from H, halogen, CN, ═O, OH, NH₂, C₃₋₆ cycloalkyl, C₁₋₄ alkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkyl; R¹¹ is selected from H, halogen, andmethyl; R¹² is selected from H, C₁₋₄ alkyl (optionally substituted withhalogen, hydroxy, alkoxy, carboxy, alkoxycarbonyl, and arylalkyloxy),—(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4-10-membered heterocycle,wherein said carbocycle and heterocycle are optionally substituted withR¹³; R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; n is, independently at each occurrence, selected from 0, 1, 2,3, and 4; p is, independently at each occurrence, selected from 0, 1,and 2; provided the following compounds are excluded


2. The compound of claim 1 having Formula (IIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein: ring A is selected from aryl and a 5- to6-membered heterocycle comprising: carbon atoms and 1-3 heteroatomsselected from N, NH, and N(C₁₋₄ alkyl); ring B is selected fromimidazole, pyridine, pyridone, pyrimidine, and pyridazine; X^(1a) isselected from C₂₋₄ alkylene and C₂₋₄ alkenylene wherein said C₂₋₄alkylene and C₂₋₄ alkenylene are optionally substituted with R⁴ and R⁵;alternatively, one or more of the carbon atoms of said alkylene may bereplaced by O and C═O; U, V, W, and Q are each independently selectedfrom N, NR⁹, S, O, C, CR², and CHR²; --- is an optional bond; R¹ is,independently at each occurrence, selected from H, halogen, NO₂, C₁₋₆alkyl, OH, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and CN; R² isselected from H, ═O, OH, NH₂, CF₃, halogen, C₁₋₄ alkyl (optionallysubstituted with OH), C₁₋₃ alkoxy, and C(O)C₁₋₃ alkyl; R³ is H; R⁴ andR⁵ are independently selected from H, halogen, C₁₋₆ alkyl, OH, and NH₂;when R⁴ and R⁵ are not attached to the same carbon atom, they may betaken together with the carbon atoms to which they are attached to forma carbocycle; R⁶ is selected from H, halogen, C(O)OH, and C(O)O(C₁₋₄alkyl); R⁷ is selected from H, C₁₋₄ alkyl, and CF₃; alternatively, R⁶and R⁷ together are ═O; R⁸ is, independently at each occurrence,selected from H, halogen, haloalkyl, CN, —(CH₂)_(n)OH, NR¹²R¹², C(O)OH,—(CH₂)_(n)—NHC(O)OR¹², —NHC(O)R¹², —NHC(O)NR¹²R¹², —NHS(O)₂C₁₋₄ alkyl,—(CH₂)_(n)—CONR¹²R¹², —(CH₂)_(n)C(O)O(C₁₋₄ alkyl), —(CH₂)_(n)—C₃₋₁₀carbocycle, and —(CH₂)_(n)-4-10-membered heterocycle optionallysubstituted with R¹³; R⁹ is selected from H and C₁₋₄ alkyl; R¹⁰ is,independently at each occurrence, selected from H, halogen, CN, ═O, OH,NH₂, C₃₋₆ cycloalkyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl; R¹¹is H; R¹² is selected from H, C₁₋₄ alkyl (optionally substituted withhalogen, hydroxy, alkoxy, carboxy, alkoxycarbonyl), —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-4-10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R¹³; R¹³ isselected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and n is, independently at each occurrence, selected from 0, 1,2, and
 3. 3. The compound of claim 2, or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate thereof, wherein: ring A isselected from phenyl, piperidine, and pyridine;

is selected from

and R¹⁰ is selected from H, F, Cl, C₁₋₄ alkyl, C₁₋₄ alkoxy, and CN.
 4. Acompound of claim 3 having Formula (IIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein:

is independently selected from

X^(1a) is selected from —CR⁴R⁵—CR⁴R⁵—, —CR⁴R⁵—CR⁴R⁵—CR⁴R⁵—, and—CR⁴═CR⁵CR⁴R⁵—, wherein one or more —CR⁴R⁵— may be replaced by O or C═O;U, V, W, and Q are each independently selected from N, NR⁹, S, C, CR²,and CHR²; R^(1a) and R^(1b) are each independently selected from H,halogen, OH, CN, CH₃, OCH₃, CF₃, and OCHF₂; R² is selected from H, NH₂,CF₃, halogen, and C₁₋₄ alkyl (optionally substituted with OH), C₁₋₃alkoxy, and C(O)C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, OH, and C₁₋₄alkyl; R⁵ is selected from H, F, and C₁₋₄ alkyl; R⁶ is independentlyselected from H, C(O)OH, and C(O)O(C₁₋₄ alkyl); R⁷ is selected from H,C₁₋₄ alkyl, and CF₃; alternatively, R⁶ and R⁷ together are ═O; R⁸ is,independently at each occurrence, selected from H, halogen, haloalkyl,CN, —(CH₂)_(n)OH, NR¹²R¹², —CH₂NH₂, C(O)OH, and —NHC(O)OR¹²,—(CH₂)_(n)—C₃₋₁₀ carbocycle, and —(CH₂)_(n)-4-10-membered heterocycleoptionally substituted with R¹³; R⁹ is selected from H and C₁₋₄ alkyl;R¹⁰ is selected from H, halogen, methyl, ethyl, methoxy, ethoxy, and CN;R¹² is selected from H, C₁₋₄ alkyl (optionally substituted with F, OH,—O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)), —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-4-10-membered heterocycle, wherein saidcarbocycle and heterocycle are optionally substituted with R¹³; R¹³ isselected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and n is, independently at each occurrence, selected from 0, 1,2, and
 3. 5. The compound of claim 4 having Formula (IVa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein:

is independently selected from

W and Q are each independently selected from N and CR²; R^(1a) isselected from H, F, and Cl; R^(1b) is selected from H, F, Cl, OH, CN,CH₃, OCH₃, CF₃, and OCHF₂; R² is selected from H, NH₂, CF₃, F, Cl, andC₁₋₄ alkyl; R⁴ is selected from H, F, methyl, ethyl, propyl, andisopropyl; R⁵ is H and F; R⁸ is, independently at each occurrence,selected from H, halogen, haloalkyl, CN, —(CH₂)_(n)OH, NR¹²R¹², C(O)OH,and —NHC(O)OR¹²; R¹⁰ is selected from H, halogen, methyl, ethyl,methoxy, ethoxy, and CN; R¹² is selected from H, C₁₋₄ alkyl (optionallysubstituted with F, OH, —O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)),—(CH₂)_(n)—C₃₋₁₀ carbocycle and —(CH₂)_(n)-4-10-membered heterocycle,wherein said carbocycle and heterocycle are optionally substituted withR¹³; R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and n is, independently at each occurrence, selected from 0, 1,2, and
 3. 6. The compound of claim 5 having Formula (Va):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein:

is independently selected from

Q is selected from N and CR²; R^(1a) is selected from H and F; R^(1b) isCl; R² is selected from H, NH₂, F, Cl, and methyl; R⁴ is selected fromH, OH, methyl, ethyl, and isopropyl; R⁵ is H and F; R⁸ is, independentlyat each occurrence, selected from H, —(CH₂)_(n)OH, NR¹²R¹², C(O)OH, and—NHC(O)OR^(u); R¹⁰ is selected from H, halogen, methyl, ethyl, methoxy,ethoxy, and CN; R¹² is selected from H, C₁₋₄ alkyl (optionallysubstituted with F, OH, —O(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)),—(CH₂)_(n)—C₃₋₁₀ carbocycle, and —(CH₂)_(n)-4-10-membered heterocycle,wherein said carbocycle and heterocycle are optionally substituted withR¹³; R¹³ is selected from OH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl,and ═O; and n is, independently at each occurrence, selected from 0, 1,2, and
 3. 7. The compound of claim 5 having Formula (VIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein:

is independently selected from

R^(1a) is selected from H and F; R^(1b) is Cl; R² is selected from H,NH₂, F, Cl, and methyl; R⁴ is selected from H, OH, methyl, ethyl, andisopropyl; R⁵ is H and F; R⁸ is, independently at each occurrence,selected from H, —(CH₂)_(n)OH, NR¹²R¹², C(O)OH, and —NHC(O)OR¹²; R¹⁰ isselected from H, halogen, methyl, ethyl, methoxy, ethoxy, and CN; R¹² isselected from H, C₁₋₄ alkyl (optionally substituted with F, OH, —O(C₁₋₄alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl)), —(CH₂)_(n)—C₃₋₁₀ carbocycle and—(CH₂)_(n)-4-10-membered heterocycle, wherein said carbocycle andheterocycle are optionally substituted with R¹³; R¹³ is selected fromOH, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, and ═O; and n is,independently at each occurrence, selected from 0, 1, 2, and
 3. 8. Thecompound of claim 4 having Formula (VIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein:

is independently selected from

W is selected from N and CR²; Q is selected from N and CR²; R^(1a) isselected from H and F; R^(1b) is Cl; R² is selected from H, Cl, NH₂, andmethyl; R⁴ is selected from H, F, methyl, ethyl, OH; R⁵ is selected fromH and F; R⁸ is selected from H, NHR¹², —(CH₂)_(n)OH, —NHC(N—CN)NHR¹²,—C(O)OH, —NHC(O)OR¹², and —(CH₂)_(n)-4-10-membered heterocycleoptionally substituted with R¹³; R¹⁰ is selected from H, F, Cl, Ci-2alkyl, methoxy, ethoxy, and CN; R¹² is selected from H, C₁₋₄ alkyl(optionally substituted with F, OH, —OC₁₋₄ alkyl, —C(O)OH, —C(O)OC₁₋₄alkyl, —O-arylalkyl), —(CH₂)_(n)—C₃₋₆ cycloalkyl and—(CH₂)_(n)-4-6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), and O wherein saidheterocycle is optionally substituted with R¹³; R¹³ is selected from OH,OC₁₋₄ alkyl, C₁₋₆ alkyl (optionally substituted with alkoxy), C₃₋₆cycloalkyl, and ═O; and n is, independently at each occurrence, selectedfrom 0, 1, 2, and
 3. 9. The compound of claim 8, or a stereoisomer, atautomer, a pharmaceutically acceptable salt, a solvate thereof,wherein:

is independently selected from

W is selected from N and CR²; Q is selected from N and CR²; R^(1a) isselected from H and F; R^(1b) is Cl; R² is selected from H, Cl, NH₂, andmethyl; R⁴ is selected from H, F, methyl, ethyl, OH; R⁵ is selected fromH and F; R⁸ is selected from H, NHR¹², —C(O)OH, and —NHC(O)OR¹²; R¹⁰ isselected from H, F, Cl, methyl, methoxy, ethoxy, and CN; R¹² is selectedfrom H, C₁₋₄ alkyl (optionally substituted with F, OH, —OC₁₋₄ alkyl,—C(O)OH, —C(O)OC₁₋₄ alkyl), —(CH₂)_(n)—C₃₋₆ cycloalkyl and—(CH₂)_(n)-4-6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), and O wherein saidheterocycle is optionally substituted with R¹³; R¹³ is selected from OH,OC₁₋₄ alkyl, C₁₋₆ alkyl (optionally substituted with alkoxy), C₃₋₆cycloalkyl, and ═O; and n is, independently at each occurrence, selectedfrom 0, 1, 2, and
 3. 10. A pharmaceutical composition comprising one ormore compounds according to claim 1 and a pharmaceutically acceptablecarrier or diluent.
 11. A method for the treatment and/or prophylaxis ofa thromboembolic disorder, comprising: administering to a patient inneed thereof a therapeutically effective amount of a compound of claim1, or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof.
 12. A method according to claim 11, wherein the thromboembolicdisorder is selected from the group consisting of arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart or in the peripheral circulation.
 13. A method according toclaim 12, wherein the thromboembolic disorder is selected from unstableangina, an acute coronary syndrome, atrial fibrillation, myocardialinfarction, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis.
 14. A compound of claim 1,or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, for use in therapy.